Nucleic acid vaccines

ABSTRACT

The invention relates to compositions and methods for the preparation, manufacture and therapeutic use ribonucleic acid vaccines (NAVs) comprising polynucleotide molecules encoding one or more antigens.

RELATED APPLICATIONS

This Application is a continuation of U.S. application Ser. No. 16/036,318, filed Jul. 16, 2018, entitled “NUCLEIC ACID VACCINES: which is a continuation of U.S. application Ser. No. 15/089,050, filed Apr. 1, 2016, entitled “NUCLEIC ACID VACCINES”, which is a continuation of International Patent Application Serial No. PCT/US2015/027400, filed Apr. 23, 2015, entitled “NUCLEIC ACID VACCINES”, which is a Non-Prov of Prov (35 USC 119(e)) of U.S. Application Ser. No. 62/088,994, filed Dec. 8, 2014, entitled “NUCLEIC ACID VACCINES” and of U.S. Application Ser. No. 61/983,250, filed Apr. 23, 2014, entitled “NUCLEIC ACID VACCINES”. The entire contents of these applications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of vaccines, specifically nucleic acid vaccines (NAVs). In particular, the invention relates to compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of ribonucleic acid (RNA) vaccines, e.g., mRNA vaccines.

BACKGROUND OF THE INVENTION

Vaccination is an effective way to provide phrophylactic protection against infectious diseases, including, but not limited to, viral, bacterial, and/or parasitic diseases, such as influenza, AIDS, hepatotisis virus infection, cholera, malaria and tuberculosis, and many other diseases. For example, influenza infections are the seventh leading cause of death in the United States with 200, 000 hospitalizations and 40,000 deaths seen in the United States per year and cause about 3-5 million hospitalizations and about 300,000 to 500,000 deaths worldwide per year. Millions of people receive flu vaccines to protect them from seasonal flu each year. Vaccination can also rapidly prevent the spread of an emerging influenze pandemic.

A typical vaccine contains an agent that resembles a weakened or dead form of the disease-causing agent, which could be a microorganism, such as bacteria, virus, fungi, parasites, or one or more toxins and/or one or more proteins, for example, surface proteins, (i.e., antigens) of such a microorganism. The antigen or agent in the vaccine can stimulate the body's immune system to recognize the agent as a foreign invader, generate antibodies against it, destroy it and develop a memory of it. The vaccine-induced memory enables the immune system to act quickly to protect the body from any of these agents that it later encounters.

Vaccine production used in the art e.g., antigen vaccine production, has several stages, including the generation of antigens, antigen purification and inactivation, and vaccine formulation. First, the antigen is generated through culturing viruses in cell lines, growing bacteria in bioreactors, or producing recombinant proteins derived from viruses and bacteria in cell cultures, yeast or bacteria. Recombinant proteins are then purified and the viruses and bacteria are inactivated before they are formulated with adjuvants in vaccines. It has been a challenge to drastically reduce the time and expense associated with current technologies in vaccine development.

Another obstacle to the development of new vaccine is the constant evolution of most infectious agents, such as viruses and bacteria. Viruses often mutate their surface proteins to generate new antigens which can help them skipping the active immune system that has been immunized by vaccines containing the viruses. In contrast, bacteria acquire and mutate key proteins to evade host defense and effective antibiotic applications.

For example, influenza A, B and C viruses are the etiological agents of influenza. Hemagglutinin (HA), the major envelop glycoprotein of influenza A and B viruses, or its homologue, hemagglutinin-esterase (HE) in influenza C virus, is the natural reservoir of the viruses. The rapid evolution of the hemagglutinin (HA) protein of the influenza virus results in the constant emergence of new strains, rendering the adaptive immune response of the host only partially protective to new infections. The biggest challenge for therapy and prophylaxis against influenza and other infections using traditional vaccines is the limitation of vaccines in breadth, providing protection only against closely related subtypes. In addition, today's length of the production process inhibits any fast reaction to develop and produce an adapted vaccine in a pandemic situation.

It is of great interest to develop new vaccines as well as new approaches to combatting infectious disease and infectious agents.

SUMMARY OF THE INVENTION

Described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs). In particular, described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines, e.g., RNA vaccines and mRNA vaccines.

The present invention provides compositions, e.g., pharmaceutical compositions, comprising one or more onucleic acid vaccines or NAVs.

The NAVs or NAV compositions or the invention may be designed to comprise one or more nucleic acid molecules, e.g., polynucleotides, which encode one or more wild type or engineered proteins, peptides or polypeptides (e.g., antigens). In some embodiments, the nucleic acid molecule, e.g., polynucleotide, is RNA. In some embodiments the nucleic acid molecule, e.g., polynucleotide, is an mRNA. In some embodiments the NAV or NAV composition comprises a nucleic acid (e.g., a RNA polynucleotide) which is chemically modified. In some embodiments the infectious agent from which the antigen is derived or engineered includes, but is not limited to viruses, bacteria, fungi, protozoa, and/or parasites.

In some embodiments are provided methods of inducing, eliciting, boosting or triggering an immune response in a cell, tissue or organism, comprising contacting said cell, tissue or organism with any of the RNAVs described or taught herein.

Aspects of the invention provide nucleic acid vaccines (NAVs) comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, formulated within a cationic lipid nanoparticle. Some aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, formulated in a carrier having a molar ratio of about 20-60% cationic lipid: 5-25% non-cationic lipid: 25-55% sterol; and 0.5-15% PEG-modified lipid.

In some embodiments, the cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319). In some embodiments, the cationic lipid nanoparticle has a molar ratio of about 20-60% cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5-15% PEG-modified lipid. In some embodiments, the cationic lipid nanoparticle comprises a molar ratio of about 50% cationic lipid, about 1.5% PEG-modified lipid, about 38.5% cholesterol and about 10% non-cationic lipid. In some embodiments, the cationic lipid nanoparticle comprises a molar ratio of about 55% cationic lipid, about 2.5% PEG lipid, about 32.5% cholesterol and about 10% non-cationic lipid. In some embodiments, the cationic lipid is an ionizable cationic lipid and the non-cationic lipid is a neutral lipid, and the sterol is a cholesterol. In some embodiments, the cationic lipid nanoparticle has a molar ratio of 50:38.5:10:1.5 of cationic lipid: cholesterol: PEG2000-DMG:DSPC.

In some embodiments, the cationic lipid nanoparticle has a mean diameter of 50-150 nm. In some embodiments, the cationic lipid nanoparticle has a mean diameter of 80-100 nm. In some embodiments, the vaccine includes 1.5 mg/mL of RNA polynucleotide and 35-45 mg/mL lipids. In some embodiments, the NAV includes about 2 mg/mL of RNA polynucleotide and about 40 mg/mL lipids.

In some embodiments, the open reading frame is codon-optimized. In some embodiments, the first antigenic polypeptide is derived from an infectious agent. In some embodiments, the infectious agent is selected from a member of the group consisting of strains of viruses and strains of bacteria. In some embodiments, the one or more RNA polynucleotides encode a further antigenic polypeptide. In some embodiments, the further RNA polynucleotide comprises at least one chemical modification and a codon-optimized open reading frame, said open reading frame encoding an antigenic polypeptide.

In some embodiments, the one or more antigenic polypeptide is selected from those proteins listed in Tables 6-16, Tables 29-30, or fragments thereof. In some embodiments, the open reading frame of the one or more RNA polynucleotides and/or the open reading frame of the second RNA polynucleotide each, independently, encodes an antigenic polypeptide selected from Tables 6-16, Tables 29-30, or fragments thereof. In some embodiments, each of the open reading frame of the one or more RNA polynucleotides is selected from any of the RNA sequences Table 28, or fragments thereof.

In any of the embodiments provided herein, the infectious agent is a strain of virus selected from the group consisting of adenovirus; Herpes simplex, type 1; Herpes simplex, type 2; encephalitis virus, papillomavirus, Varicella-zoster virus; Epstein-barr virus; Human cytomegalovirus; Human herpes virus, type 8; Human papillomavirus; BK virus; JC virus; Smallpox; polio virus; Hepatitis B virus; Human bocavirus; Parvovirus B19; Human astrovirus; Norwalk virus; coxsackievirus; hepatitis A virus; poliovirus; rhinovirus; Severe acute respiratory syndrome virus; Hepatitis C virus; Yellow Fever virus; Dengue virus; West Nile virus; Rubella virus; Hepatitis E virus; Human Immunodeficiency virus (HIV); Influenza virus; Guanarito virus; Junin virus; Lassa virus; Machupo virus; Sabiá virus; Crimean-Congo hemorrhagic fever virus; Ebola virus; Marburg virus; Measles virus; Mumps virus; Parainfluenza virus; Respiratory syncytial virus; Human metapneumovirus; Hendra virus; Nipah virus; Rabies virus; Hepatitis D; Rotavirus; Orbivirus; Coltivirus; Banna virus; Human Enterovirus; Hanta virus; West Nile virus; Middle East Respiratory Syndrome Corona Virus; Japanese encephalitis virus; Vesicular exanthernavirus; and Eastern equine encephalitis.

In some embodiments, the virus is a strain of Influenza A or Influenza B or combinations thereof. In some embodiments, the strain of Influenza A or Influenza B is associated with birds, pigs, horses, dogs, humans or non-human primates. In some embodiments, the antigenic polypeptide encodes a hemagglutinin protein or fragment thereof. In some embodiments, the hemagglutinin protein is H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, H18, or a fragment thereof. In some embodiments, the hemagglutinin protein does not comprise a head domain (HA1). In some embodiments, the hemagglutinin protein comprises a portion of the head domain (HA1). In some embodiments, the hemagglutinin protein does not comprise a cytoplasmic domain. In some embodiments, the hemagglutinin protein comprises a portion of the cytoplasmic domain. In some embodiments, the truncated hemagglutinin protein. In some embodiments, the truncated hemagglutinin protein comprises a portion of the transmembrane domain. In some embodiments, the amino acid sequence of the hemagglutinin protein or fragment thereof comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, or 99% identify with any of the amino acid sequences provided in Table 6-14. In some embodiments, the virus is selected from the group consisting of H1N1, H3N2, H7N9, and H10N8. In some embodiments, the antigenic polypeptide is selected from those proteins listed in Tables 6-14, or fragments thereof.

In some embodiments, the infectious agent is a strain of bacteria selected from Tuberculosis (Mycobacterium tuberculosis), clindamycin-resistant Clostridium difficile, fluoroquinolon-resistant Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Enterococcus faecalis, multidrug-resistant Enterococcus faecium, multidrug-resistance Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and vancomycin-resistant Staphylococcus aureus (VRSA). In some embodiments, the bacteria is Clostridium difficile.

In some embodiments, the NAV is multivalent. In some embodiments, the open reading frame of the one or more RNA polynucleotides encode at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 antigenic polypeptides. In some embodiments, the open reading frame of the one or more RNA polynucleotides encode at least 10, 15, 20 or 50 antigenic polypeptides. In some embodiments, the open reading frame of the one or more RNA polynucleotides encode 2-10, 10-15, 15-20, 20-50, 50-100 or 100-200 antigenic polypeptides.

In some embodiments, the RNA polynucleotide includes a chemical modification and the chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcyto sine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, Dihydropseudouridine, 5-methoxyuridine and 2′-O-methyl uridine. In some embodiments, the RNA polynucleotide includes a second chemical modification wherein said second chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the combination of first and second chemical modification is selected from those listed in Table 25.

Other aspects provide a NAV comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, formulated within a nanoparticle, wherein the nanoparticle has a mean diameter of 50-200 nm. In some embodiments, the nanoparticle has a polydiversity value of less than 0.4. In some embodiments, the nanoparticle has a net neutral charge at a neutral pH. In some embodiments, the nanoparticle has a mean diameter of 80-100 nm. In some embodiments, the nanoparticle is a cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319).

Other aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein at least 80% of the uracil in the open reading frame have a chemical modification. In some embodiments, 100% of the uracil in the open reading frame have a chemical modification. In some embodiments, the chemical modification is in the 5-position of the uracil. In some embodiments, the chemical modification is a N1-methyl pseudouridine. In some embodiments, the nucleic acid vaccine is formulated within a cationic lipid complex or cationic lipid nanoparticle.

Yet other aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, at least one 5′ terminal cap and at least one chemical modification, formulated within a cationic lipid nanoparticle. In some embodiments, the 5′ terminal cap is 7mG(5′)ppp(5′)NlmpNp. In some embodiments, the chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, Dihydropseudouridine, 5-methoxyuridine and 2′-O-methyl uridine. In some embodiments, the RNA polynucleotide further comprises a second chemical modification wherein said second chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the combination of first and second chemical modification is selected from those listed in Table 25.

In some embodiments, the cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319). In some embodiments, the cationic lipid nanoparticle has a molar ratio of about 20-60% cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5-15% PEG-modified lipid.

Some aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a hemagglutinin protein and a pharmaceutically acceptable carrier or excipient, formulated within a cationic lipid nanoparticle. In some embodiments, the hemagglutinin protein is selected from HAL HA7 and HA10. In some embodiments, the RNA polynucleotide does not encode F protein. In some embodiments, the RNA polynucleotide further encodes neuraminidase protein. In some embodiments, the hemagglutinin protein is derived from a strain of Influenza A virus or Influenza B virus or combinations thereof. In some embodiments, the Influenza virus is selected from H1N1, H3N2, H7N9, and H10N8.

In some embodiments, the RNA polynucleotide includes a chemical modification and the chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, Dihydropseudouridine, 5-methoxyuridine and 2′-O-methyl uridine. In some embodiments, the RNA polynucleotide further comprises a second chemical modification wherein said second chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the combination of first and second chemical modification is selected from those listed in Table 25.

In some embodiments, the cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319). In some embodiments, the cationic lipid nanoparticle has a molar ratio of about 20-60% cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5-15% PEG-modified lipid.

In some embodiments, the RNA polynucleotide comprises SEQ ID NOs 197-392. In some embodiments, the RNA polynucleotide comprises a polynucleotide having at least 80% sequence identity to SEQ ID NOs 197-392. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 941. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO941. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 946. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 946. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 1022. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 1022. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 1023. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 1023. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1024. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1024. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1025. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1025. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1026. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1026. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1027. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1027.

Aspects of the invention provide nucleic acids comprising 80-95% sequence identity to SEQ ID NO 1027 or SEQ ID NO 1026. Other aspects provide a nucleic acid comprising SEQ ID NO: 395.

Yet other aspects provide a method of inducing an antigen specific immune response in a subject comprising administering any of the vaccines described herein to the subject in an effective amount to produce an antigen specific immune response. In some embodiments, the antigen specific immune response comprises a T cell response. In some embodiments, the antigen specific immune response comprises a B cell response. In some embodiments, the method of producing an antigen specific immune response involves a single administration of the vaccine. In some embodiments, the method further comprises administering a booster dose of the vaccine. In some embodiments, the vaccine is administered to the subject by intradermal or intramuscular injection.

In some embodiments, the booster dose of the vaccine is administered to the subject on day twenty one. In some embodiments, a dosage of between 10 ug/kg and 400 ug/kg of the vaccine is administered to the subject. In some embodiments, a dosage of 25 micrograms of the RNA polynucleotide is included in the vaccine administered to the subject. In some embodiments, a dosage of 100 micrograms of the RNA polynucleotide is included in the vaccine administered to the subject. In some embodiments, a dosage of 400 micrograms of the RNA polynucleotide is included in the vaccine administered to the subject. In some embodiments, the RNA polynucleotide accumulates at a 100 fold higher level in the local lymph node in comparison with the distal lymph node.

Aspects provide methods of preventing or treating influenza viral infection comprising administering to a subject any of the vaccines described herein. In some embodiments, the antigen specific immune response comprises a T cell response. In some embodiments, the antigen specific immune response comprises a B cell response. In some embodiments, the method of producing an antigen specific immune response involves a single administration of the vaccine. In some embodiments, the vaccine is administered to the subject by intradermal or intramuscular injection.

Yet other aspects provide methods of vaccinating a subject comprising administering to the subject a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and wherein an adjuvant is not coformulated or co-administered with the vaccine. In some embodiments, a dosage of between 10 ug/kg and 400 ug/kg of the nucleic acid vaccine is administered to the subject. In some embodiments, the nucleic acid vaccine is administered to the subject by intradermal or intramuscular injection. In some embodiments, the nucleic acid vaccine is administered to the subject on day zero. In some embodiments, a second dose of the nucleic acid vaccine is administered to the subject on day twenty one.

In some embodiments, a dosage of 25 micrograms of the RNA polynucleotide is included in the nucleic acid vaccine administered to the subject. In some embodiments, a dosage of 100 micrograms of the RNA polynucleotide is included in the nucleic acid vaccine administered to the subject. In some embodiments, a dosage of 400 micrograms of the RNA polynucleotide is included in the nucleic acid vaccine administered to the subject. In some embodiments, the RNA polynucleotide accumulates at a 100 fold higher level in the local lymph node in comparison with the distal lymph node.

Aspects of the invention provide a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and a pharmaceutically acceptable carrier or excipient, wherein an adjuvant is not included in the vaccine. In some embodiments, the stabilization element is a histone stem-loop. In some embodiments, the stabilization element is a nucleic acid sequence having decreased GC content relative to wild type sequence.

Aspects of the invention provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in the formulation for in vivo administration to a host, which confers an antibody titer superior to the criterion for seroprotection for the first antigen for an acceptable percentage of human subjects. In some embodiments, the antibody titer is a neutralizing antibody titer.

Also provided are NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host for eliciting a longer lasting high antibody titer than an antibody titer elicited by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to produce a neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from a cationic peptide and an immunostimulatory nucleic acid. In some embodiments, the cationic peptide is protamine.

Aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in the formulation for in vivo administration to a host such that the level of antigen expression in the host significantly exceeds a level of antigen expression produced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide.

Other aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding a first antigenic polypeptide, wherein the vaccine has at least 10 fold less RNA polynucleotide than is required for an unmodified mRNA vaccine to produce an equivalent antibody titer. In some embodiments, the RNA polynucleotide is present in a dosage of 25-100 micrograms.

Aspects of the invention also provide a unit of use vaccine, comprising between 10 ug and 400 ug of one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding a first antigenic polypeptide, and a pharmaceutically acceptable carrier or excipient, formulated for delivery to a human subject. In some embodiments, the vaccine further comprises a cationic lipid nanoparticle.

Aspects of the invention provide methods of creating, maintaining or restoring antigenic memory to an influenza strain in an individual or population of individuals comprising administering to said individual or population an antigenic memory booster nucleic acid vaccine comprising (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemical modification and two or more codon-optimized open reading frames, said open reading frames encoding a set of reference antigenic polypeptides, and (b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the vaccine is administered to the individual via a route selected from the group consisting of intramuscular administration, intradermal administration and subcutaneous administration. In some embodiments, the administering step comprises contacting a muscle tissue of the subject with a device suitable for injection of the composition. In some embodiments, the administering step comprises contacting a muscle tissue of the subject with a device suitable for injection of the composition in combination with electroporation.

Aspects of the invention provide methods of vaccinating a subject comprising administering to the subject a single dosage of between 25 ug/kg and 400 ug/kg of a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide in an effective amount to vaccinate the subject.

Aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a hemagglutinin protein fragment, wherein the hemagglutinin protein includes only a portion of at least one of: a head domain (HA1), a cytoplasmic domain, or a transmembrane domain. In some embodiments, the hemagglutinin protein is H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, H18. In some embodiments, the hemagglutinin protein does not comprise the head domain (HA1). In some embodiments, the hemagglutinin protein does not comprise the cytoplasmic domain. In some embodiments, the truncated hemagglutinin protein does not comprise the transmembrane domain. In some embodiments, the amino acid sequence of the hemagglutinin protein comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, or 99% identify with any of the amino acid sequences provided in Tables 6-16.

In some embodiments, the vaccine is formulated within a cationic lipid complex or cationic lipid nanoparticle. In some embodiments, the polynucleotide comprises at least one 5′ terminal cap and at least one chemical modification.

Aspects also provide any of the vaccines described herein for use in a method of inducing an antigen specific immune response in a subject. In some embodiments, the method comprises administering the vaccine to the subject in an effective amount to produce an antigen specific immune response.

Other aspects provide a use of any of the vaccines described herein in the manufacture of a medicament for use in a method of inducing an antigen specific immune response in a subject, the method comprising administering the vaccine to the subject in an effective amount to produce an antigen specific immune response.

Aspects also provide for any of the vaccines described herein for use in a method of preventing or treating influenza viral infection, the method comprising administering the vaccine to a subject.

Other aspects provide a use any of the vaccines described herein in the manufacture of a medicament for use in a method of preventing or treating influenza viral infection, the method comprising administering the vaccine to a subject.

Other aspects provide nucleic acid vaccines for use in a method of vaccinating a subject wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and wherein an adjuvant is not coformulated or co-administered with the vaccine. In some embodiments, the method further comprises administering the vaccine to the subject.

Other aspects provide a use of a nucleic acid vaccine in the manufacture of a medicament for use in a method of vaccinating a subject wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and wherein an adjuvant is not coformulated or co-administered with the vaccine. In some embodiments, the method further comprises administering the vaccine to the subject.

Aspects of the invention provide an antigenic memory booster nucleic acid vaccine for use in a method of creating, maintaining or restoring antigenic memory to an influenza strain in an individual or population of individuals. In some embodiments, the antigenic memory booster nucleic acid vaccine comprises (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemical modification and two or more codon-optimized open reading frames, said open reading frames encoding a set of reference antigenic polypeptides, and (b) optionally a pharmaceutically acceptable carrier or excipient; and wherein the method comprises administering to said individual or population the antigenic memory booster nucleic acid vaccine.

Other aspects provide a use of an antigenic memory booster nucleic acid vaccine in the manufacture of a medicament for use in a method of creating, maintaining or restoring antigenic memory to an influenza strain in an individual or population of individuals, wherein the antigenic memory booster nucleic acid vaccine comprises (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemical modification and two or more codon-optimized open reading frames, said open reading frames encoding a set of reference antigenic polypeptides, and (b) optionally a pharmaceutically acceptable carrier or excipient; and wherein the method comprises administering to said individual or population the antigenic memory booster nucleic acid vaccine.

Other aspects provide a nucleic acid vaccine for use in a method of vaccinating a subject, wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, and wherein the method comprises administering to the subject a single dosage of between 25 ug/kg and 400 ug/kg of the nucleic acid vaccine in an effective amount to vaccinate the subject.

Other aspects provide a use of a nucleic acid vaccine in the manufacture of a medicament for use in a method of vaccinating a subject, wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, and wherein the method comprises administering to the subject a single dosage of between 25 ug/kg and 400 ug/kg of the nucleic acid vaccine in an effective amount to vaccinate the subject.

In some embodiments, the NAV polynucleotides may encode one or more polypeptides of an influenza strain as an antigen. Such antigens include, but are not limited to those antigens encoded by the polynucleotides listed in the Tables presented herein. In the table, the GenBank Accession Number or GI Accession Number represents either the complete or partial CDS of the encoded antigen. The NAV polynucleotides may comprise a region of any of the sequences listed in the tables or entire coding region of the mRNA listed. They may comprise hybrid or chimeric regions, or mimics or variants.

The details of various embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages will be apparent from the following description of particular embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of various embodiments of the invention.

FIGS. 1A and 1B are schematics of a polynucleotide construct. FIG. 1A is a schematic of a polynucleotide construct taught in commonly owned co-pending U.S. patent application Ser. No. 13/791,922 filed Mar. 9, 2013, the contents of which are incorporated herein by reference. FIG. 1B is a schematic of a linear polynucleotide construct.

FIG. 2 is a schematic of a series of chimeric polynucleotides of the present invention.

FIG. 3 is a schematic of a series of chimeric polynucleotides illustrating various patterns of positional modifications and showing regions analogous to those regions of an mRNA polynucleotide.

FIG. 4 is a schematic of a series of chimeric polynucleotides illustrating various patterns of positional modifications based on Formula I.

FIG. 5 is a is a schematic of a series of chimeric polynucleotides illustrating various patterns of positional modifications based on Formula I and further illustrating a blocked or structured 3′ terminus.

FIGS. 6A and 6B are schematics of circular constructs of the present invention.

FIGS. 7A-7B are schematics of circular constructs of the present invention.

FIGS. 8A-8B are schematics of a circular constructs of the present invention. FIG. 8A shows a circular construct comprising at least one sensor region and a spacer region. FIG. 8B shows a non-coding circular construct.

FIG. 9 is a schematic of a non-coding circular construct of the present invention.

FIG. 10 shows HA neutralization titres of a chemically modified mRNA influenza vaccine in comparison with protein and unmodified mRNA vaccines.

FIG. 11 shows hemagglutinin inhibition titers in mice following vaccination with different doses and formulations of mRNA encoding the hemagglutinin protein of the H1N1 virus.

FIGS. 12A-12D show percent survival of mice after vaccination and challenge with influenza A/PR/8/34 virus. FIG. 12A shows percent survival at 1 week post challenge. FIG. 12B shows percent survival at 2 weeks post challenge. FIG. 12C shows percent survival at 3 weeks post challenge. FIG. 12D shows percent survival at 4 weeks post challenge.

FIG. 13 shows the mean hemaglutination inhibition titers of mice after vaccination and challenge with influenza A/PR/8/34 virus

FIGS. 14A-14C shows CD4 T cell IFNγ cytokine responses. FIG. 14A shows IFNγ production upon H1 protein/peptide stimulation. FIG. 14B shows IFNγ production upon H7 protein/peptide stimulation. FIG. 14C shows IFNγ production upon PMA+ionomycin stimulation.

FIGS. 15A-15D shows IgG production following H1 and H7 protein/peptide stimulation.

FIG. 16 is a graph showing hemagglutinin inhibition titers (HAI) against H10 following administration of the H10N8/N1-methyl pseudouridine/C0 formulation MC3 vaccine at the indicated dosages.

FIG. 17 is a graph showing hemagglutinin inhibition titers (HAI) against H10 following administration of the H10N8/N1-methyl pseudouridine/C1 formulation MC3 vaccine at the indicated dosages.

FIG. 18 is a graph comparing hemagglutinin inhibition titers (HAI) against H7 following administration of 10 μg/dose of the H7N9/C0 formulation compared to the H7N9/C1 formulation.

FIG. 19 is a graph of the mean hemagglutinin inhibition titers (HAI) in serum samples from cynomolgus monkey at various time points prior to and after administration of the indicated formulations and dosages.

FIG. 20 is a graph showing the H7N9 viral load in ferrets challenged at day 21 after receiving a single immunization.

FIGS. 21A-21D present mouse survival and HAI titers in mice challenged with a lethal dose following administration of a single dose of mRNA NAV encoding H7N9. FIG. 21A shows survival at day 7 post challenge. FIG. 21B shows survival at day 21 post challenge. FIG. 21C shows survival at day 84 post challenge. FIG. 21D shows HAI titers.

FIGS. 22-1 through 22-51 show an alignment of amino acid sequences of hemagglutinin proteins from influenza A H7N9 strains relative to a consensus sequence. The sequences, from top to bottom, correspond to SEQ ID NOs: 1020, 8, 13, 7, 98, 99, 100, 96, 89, 92, 24, 29, 90, 57, 42, 27, 78, 74, 95, 30, 31, 32, 25, 39, 38, 35, 36, 37, 82, 91, 83, 104, 93, 94, 178, 133, 134, 132, 135, 136, 173, 175, 174, 73, 70, 33, 34, 41, 40, 76, 75, 72, 79, 80, 86, 105, 77, 11, 12, 4, 164, 150, 151, 171, 152, 165, 121, 166, 167, 156, 157, 168, 143, 169, 144, 145, 122, 113, 117, 119, 138, 137, 146, 147, 148, 158, 159, 160, 161, 162, 62, 129, 130, 141, 123, 124, 176, 125, 182, 183, 179, 180, 184, 181, 185, 186, 187, 188, 189, 190, 193, 177, 140, 49, 47, 48, 97, 50, 51, 191, 195, 196, 128, 131, 170, 111, 112, 118, 108, 120, 109, 107, 26, 106, 52, 53, 28, 192, 45, 46, 6, 44, 43, 126, 19, 21, 20, 59, 54, 71, 102, 10, 101, 2, 58, 23, 55, 5, 22, 103, 153, 154, 155, 172, 142, 114, 115, 116, 127, 149, 163, 139, 194, 110, 17, 81, 3, 85, 87, 88, 84, 61, 60, 1, 9, 14, 15, 16, 64, 63, 66, 65, 67, 68, 69, 18, and 56.

FIGS. 23-1 through 23-14 (SEQ ID NOS: 1021, 967-1019) shows an alignment of amino acid sequences of hemagglutinin proteins from influenza A H10N8 strains relative to a consensus sequence.

DETAILED DESCRIPTION

It is of great interest in the fields of therapeutics, diagnostics, reagents and for biological assays to be able design, synthesize and deliver a nucleic acid, e.g., a ribonucleic acid (RNA) for example, a messenger RNA (mRNA) encoding a peptide or polypeptide of interest inside a cell, whether in vitro, in vivo, in situ or ex vivo, such as to effect physiologic outcomes which are beneficial to the cell, tissue or organ and ultimately to an organism. One beneficial outcome is to cause intracellular translation of the nucleic acid and production of at least one encoded peptide or polypeptide of interest.

Of particular interest, is the ability to design, synthesize and deliver a nucleic acid, e.g., a ribonucleic acid (RNA), for example, a messenger RNA (mRNA), which encodes an antigen, e.g., an antigen derived from an infectious microorganism, for the purpose of vaccination.

Described herein are compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs) where at least one component of the NAV is a nucleic acid molecule, e.g., a polynucleotide. In particular, described herein are compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs) where at least one component of the NAV is a polynucleotide. In particular, described herein are compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs) where at least one component of the NAV is a RNA polynucleotide, e.g., an mRNA polynucleotide which encodes an antigen, e.g., an antigen derived from an infectious microorganism. In certain embodiments, the invention relates to compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of ribonucleic acid vaccines (RNAVs) where at least one component of the RNAV is a ribonucleic acid molecule, e.g., a mRNA which encodes an antigen, e.g., an antigen derived from an infectious microorganism. As such the present invention is directed, in part, to polynucleotides, specifically in vitro transcription (IVT) polynucleotides, chimeric polynucleotides and/or circular polynucleotides which may function as a vaccine or component of a vaccine.

Also provided are systems, processes, devices and kits for the selection, design and/or utilization of the NAVs described herein.

According to the present invention, the polynucleotides may be modified in a manner as to avoid the deficiencies of or provide improvements over other polynucleotide molecules of the art.

Although attempts have been made to produce functional RNA vaccines, including mRNA vaccines and self-replicating RNA vaccines, the therapeutic efficacy of these RNA vaccines have not yet been fully established. Quite surprisingly, the inventors have discovered a class of formulations for delivering mRNA vaccines in vivo that results in significantly enhanced, and in many respects synergistic, immune responses including enhanced antigen generation and functional antibody production with neutralization capability. These results are achieved even when significantly lower doses of the mRNA are administered in comparison with mRNA doses used in other classes of lipid based formulations. The formulations of the invention have demonstrated significant unexpected in vivo immune responses sufficient to establish the efficacy of functional mRNA vaccines as prophylactic and therapeutic agents.

The invention involves, in some aspects, the surprising finding that lipid nanoparticle (LNP) formulations significantly enhance the effectiveness of mRNA vaccines, including chemically modified and unmodified mRNA vaccines. The efficacy of mRNA vaccines formulated in LNP was examined in vivo using several distinct viral antigens and in a variety of different animal models. The results presented herein demonstrate the unexpected superior efficacy of the mRNA vaccines formulated in LNP over other mRNA vaccines formulated in other lipid based carriers as well as over protein antigens.

In addition to providing an enhanced immune response, the formulations of the invention generate a more rapid immune response following a single dose of antigen than other mRNA or protein based vaccines tested. A study described herein involved intravenous (IV), intramuscular (IM), or intradermal (ID) vaccination of mice, followed by challenge with a lethal dose of virus. In addition to all of the vaccinated animals surviving the lethal dose, significantly stronger early immune responses were observed (anti-viral activity via virus neutralization assay and HA inhibition (HAI)) in comparison to protein antigen and other lipid based formulations (lipoplex). The data demonstrates that as early as 1 week after vaccination two groups of animals receiving a mRNA-LNP formulation (ID or IM) displayed HAI titers over 40, at 60 and 114, respectively. An HAI titer of greater than 40 is deemed sufficient to protect from a lethal challenge of influenza. The rapid response was unexpected, particularly when compared to the response seen with protein antigen and mRNA vaccines formulated in other lipid carriers (lipoplex), which at one week and even at three weeks following vaccination continued to show ineffective HAI titers of less than 40.

At each of the later time points (3 weeks and 5 weeks), the formulations of the invention continued to provide significantly stronger therapeutic responses than did protein antigen. In fact both chemically unmodified and modified mRNA-LNP formulation administered by IV route had enhanced HAI titers with respect to the protein antigen. By week 3, all of the animals receiving an mRNA-LNP formulation by IM or ID administration displayed HAI activity over 40, as compared to protein antigen, which at one week and three weeks continued to show HAI titers of less than 40. By week 5 a mRNA-LNP formulation administered by ID route had a surprising HAI activity of greater than 10,000, in contrast to the HAI titer of around 400 for protein antigen at that time point. Mice receiving a mRNA-LNP formulation also displayed neutralizing activity of 79-250 (IM) and 250 (ID) by microneutralization assay, in comparison to protein antigen, which had undetectable neutralization activity at that time point. By week 5 following vaccination, five of the six LNP formulated groups showed high neutralizing activity between 789 and 24892. In contrast, the mice vaccinated with protein antigen displayed neutralizing activity in only 3 of 5 mice and ranging only between 79 and 250.

The mRNA-LNP formulations of the invention also produced quantitatively and qualitatively better immune responses than did mRNA vaccines formulated in a different lipid carrier (lipoplex). At week 5 the mRNA-lipoplex vaccine produced HAI titers of 197, in comparison to those achieved by the mRNA-LNP formulations of the invention (HAI titers of 635-10,152). At all other time points and for all of the mRNA-lipoplex vaccines, none of the HAI titers reached the critical level of greater than 40. Additionally, the mRNA-lipoplex vaccines did not result in any detectable neutralizing activity in the microneutralization activity, even as late as five weeks after vaccination.

The data described herein demonstrate that the formulations of the invention produced significant unexpected improvements over both existing protein antigen vaccines and mRNA vaccine formulations, including: 100% rescue from lethal influenza challenge with rapid onset of protective antibody titers after 1 week and high antibody titers, i.e., 50 fold over unmodified mRNA and 20 fold over the protein vaccine.

Additionally, the mRNA-LNP formulations of the invention were superior to other lipid formulations even when the dose of mRNA was significantly lower than in the other lipid formulations. For instance, the data described above was generated using 10 μg of mRNA in the mRNA-LNP formulations in contrast to 80 μg of mRNA in the mRNA-lipoplex formulation.

The formulations of the invention also showed strong efficacy in several non-rodent animal models, including non-human primates. Highly effective vaccination was observed in cynomoglus monkeys and ferrets. Cynomoglus monkeys were vaccinated with various doses of mRNA-LNP formulations (50 μg/dose, 200 μg/dose, 400 μg/dose). Quite surprisingly, the vaccine formulations of the invention at all doses measured significantly reduced viral titers in the lungs of ferrets when exposed to virus just 7 days following single vaccination. Statistically significant increases in antibody titer as measured by HAI and microneutralization were detected as early as 7 days following vaccination and through the entire length of the study (84 days). A single vaccination was able to eliminate all virus in most animals.

The LNP used in the studies described herein has been used previously to deliver siRNA various in animal models as well as in humans. In view of the observations made in association with the siRNA delivery of LNP formulations, the fact that LNP is useful in vaccines is quite surprising. It has been observed that therapeutic delivery of siRNA formulated in LNP causes an undesirable inflammatory response associated with a transient IgM response, typically leading to a reduction in antigen production and a compromised immune response. In contrast to the findings observed with siRNA, the LNP-mRNA formulations of the invention are demonstrated herein to generate enhanced IgG levels, sufficient for prophylactic and therapeutic methods rather than transient IgM responses.

I. Nucleic Acid Vaccines (NAVs)

Nucleic Acid Vaccines (NAVs) of the present invention comprise one or more polynucleotides, e.g., polynucleotide constructs, which encode one or more wild type or engineered antigens. Exemplary polynucleotides, e.g., polynucleotide constructs, include antigen-encoding RNA polynucleotides, e.g., mRNAs. In exemplary aspect, polynucleotides of the invention, e.g., antigen-encoding RNA polynucleotides, may include at least one chemical modification.

NAV compositions of the invention may comprise other components including, but not limited to, tolerizing agents or adjuvants.

Tolerizing Agent or Composition

Where auto-immunity mediated side effects occur, tolerizing mRNA and/or such as any of those taught for example in U.S. Ser. No. 61/892,556 filed Oct. 18, 2013, and PCT/US2014/61104 filed Oct. 17, 2014, the contents of which are incorporated herein by reference in their entirety) are co-administered with the NAV to induce antigen specific tolerance.

Adjuvants

Adjuvants or immune potentiators, may also be administered with or in combination with one or more NAVs.

In one embodiment, an adjuvant acts as a co-signal to prime T-cells and/or B-cells and/or NK cells as to the existence of an infection.

Advantages of adjuvants include the enhancement of the immunogenicity of antigens, modification of the nature of the immune response, the reduction of the antigen amount needed for a successful immunization, the reduction of the frequency of booster immunizations needed and an improved immune response in elderly and immunocompromised vaccinees. These may be co-administered by any route, e.g., intramusculary, subcutaneous, IV or intradermal injections.

Adjuvants useful in the present invention may include, but are not limited to, natural or synthetic. They may be organic or inorganic.

Aduvants may be selected from any of the classes (1) mineral salts, e.g., aluminium hydroxide and aluminium or calcium phosphate gels; (2) emulsions including: oil emulsions and surfactant based formulations, e.g., microfluidised detergent stabilised oil-in-water emulsion, purified saponin, oil-in-water emulsion, stabilised water-in-oil emulsion; (3) particulate adjuvants, e.g., virosomes (unilamellar liposomal vehicles incorporating influenza haemagglutinin), structured complex of saponins and lipids, polylactide co-glycolide (PLG); (4) microbial derivatives; (5) endogenous human immunomodulators; and/or (6) inert vehicles, such as gold particles; (7) microorganism derived adjuvants; (8) tensoactive compunds; (9) carbohydrates; or combinations thereof.

Adjuvants for DNA nucleic acid vaccines (DNA) have been disclosed in, for example, Kobiyama, et al Vaccines, 2013, 1(3), 278-292, the contents of which are incorporated herein by reference in their entirety. Any of the adjuvants disclosed by Kobiyama may be used in the RNAVs of the present invention.

Other adjuvants which may be utilized in the RNAVs of the present invention include any of those listed on the web-based vaccine adjuvant database, Vaxjo; http://www.violinet.org/vaxjo/and described in for example Sayers, et al., J. Biomedicine and Biotechnology, volume 2012 (2012), Article ID 831486, 13 pages, the content of which is incorporated herein by reference in its entirety.

Selection of appropriate adjuvants will be evident to one of ordinary skill in the art. Specific adjuvants may include, without limitation, cationic liposome-DNA complex JVRS-100, aluminum hydroxide vaccine adjuvant, aluminum phosphate vaccine adjuvant, aluminum potassium sulfate adjuvant, alhydrogel, ISCOM(s)™, Freund's Complete Adjuvant, Freund's Incomplete Adjuvant, CpG DNA Vaccine Adjuvant, Cholera toxin, Cholera toxin B subunit, Liposomes, Saponin Vaccine Adjuvant, DDA Adjuvant, Squalene-based Adjuvants, Etx B subunit Adjuvant, IL-12 Vaccine Adjuvant, LTK63 Vaccine Mutant Adjuvant, TiterMax Gold Adjuvant, Ribi Vaccine Adjuvant, Montanide ISA 720 Adjuvant, Corynebacterium-derived P40 Vaccine Adjuvant, MPL™ Adjuvant, AS04, AS02, Lipopolysaccharide Vaccine Adjuvant, Muramyl Dipeptide Adjuvant, CRL1005, Killed Corynebacterium parvum Vaccine Adjuvant, Montanide ISA 51, Bordetella pertussis component Vaccine Adjuvant, Cationic Liposomal Vaccine Adjuvant, Adamantylamide Dipeptide Vaccine Adjuvant, Arlacel A, VSA-3 Adjuvant, Aluminum vaccine adjuvant, Polygen Vaccine Adjuvant, Adjumer™, Algal Glucan, Bay R1005, Theramide®, Stearyl Tyrosine, Specol, Algammulin, Avridine®, Calcium Phosphate Gel, CTA1-DD gene fusion protein, DOC/Alum Complex, Gamma Inulin, Gerbu Adjuvant, GM-CSF, GMDP, Recombinant hIFN-gamma/Interferon-g, Interleukin-1β, Interleukin-2, Interleukin-7, Sclavo peptide, Rehydragel LV, Rehydragel HPA, Loxoribine, MF59, MTP-PE Liposomes, Murametide, Murapalmitine, D-Murapalmitine, NAGO, Non-Ionic Surfactant Vesicles, PMMA, Protein Cochleates, QS-21, SPT (Antigen Formulation), nanoemulsion vaccine adjuvant, AS03, Quil-A vaccine adjuvant, RC529 vaccine adjuvant, LTR192G Vaccine Adjuvant, E. coli heat-labile toxin, LT, amorphous aluminum hydroxyphosphate sulfate adjuvant, Calcium phosphate vaccine adjuvant, Montanide Incomplete Seppic Adjuvant, Imiquimod, Resiquimod, AF03, Flagellin, Poly(I:C), ISCOMATRIX®, Abisco-100 vaccine adjuvant, Albumin-heparin microparticles vaccine adjuvant, AS-2 vaccine adjuvant, B7-2 vaccine adjuvant, DHEA vaccine adjuvant, Immunoliposomes Containing Antibodies to

Costimulatory Molecules, SAF-1, Sendai Proteoliposomes, Sendai-containing Lipid Matrices, Threonyl muramyl dipeptide (TMDP), Ty Particles vaccine adjuvant, Bupivacaine vaccine adjuvant, DL-PGL (Polyester poly (DL-lactide-co-glycolide)) vaccine adjuvant, IL-15 vaccine adjuvant, LTK72 vaccine adjuvant, MPL-SE vaccine adjuvant, non-toxic mutant E112K of Cholera Toxin mCT-E112K, and/or Matrix-S.

Other adjuvants which may be co-administered with the NAVs of the invention include, but are not limited to interferons, TNF-alpha, TNF-beta, chemokines such as CCL21, eotaxin, HMGB1, SA100-8alpha, GCSF, GMCSF, granulysin, lactoferrin, ovalbumin, CD-40L, CD28 agonists, PD-1, soluble PD1, L1 or L2, or interleukins such as IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-21, IL-23, IL-15, IL-17, and IL-18. These may be administered with the NAV on the same encoded polynucleotide, e.g., polycistronic, or as separate mRNA encoding the adjuvant and antigen.

Valency

NAVs of the present invention may vary in their valency. Valency refers to the number of antigenic components in the NAV or NAV polynucleotide (e.g., RNA polynucleotide) or polypeptide. In some embodiments, the NAVs are monovalent. In some embodiments, the NAVs are divalent. In some embodments the NAVs are trivalent. In some embodiments the NAVs are multi-valent. Multivalent vaccines may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more antigens or antigenic moieties (e.g., antigenic peptides, etc.). The antigenic components of the NAVs may be on a single polynucleotide or on separate polynucleotides.

Therapeutics

The NAVs of the present invention can be used as therapeutic or prophylactic agents. They are provided for use in medicine and/or for the priming of immune effector cells, e.g., stimulate/transfect PBMCs ex vivo and re-infuse the activated cells. For example, a NAV described herein can be administered to a subject, wherein the polynucleotides is translated in vivo to produce an antigen. Provided are compositions, methods, kits, and reagents for diagnosis, treatment or prevention of a disease or condition in humans and other mammals. The active therapeutic agents of the invention include NAVs, cells containing NAVs or polypeptides translated from the polynucleotides contained in said NAVs.

Provided herein are methods of inducing translation of a polypeptide (e.g., antigen or immunogen) in a cell, tissue or organism using the polynucleotides of the NAVs described herein. Such translation can be in vivo, ex vivo, in culture, or in vitro. The cell, tissue or organism is contacted with an effective amount of a composition containing a NAV which contains a polynucletotide that has at least one a translatable region encoding the polypeptide of intereste (e.g., antigen or immunogen).

An “effective amount” of the NAV composition is provided based, at least in part, on the target tissue, target cell type, means of administration, physical characteristics of the polynucleotide (e.g., size, and extent of modified nucleosides) and other components of the NAV, and other determinants. In general, an effective amount of the NAV composition provides an induced or boosted immune response as a function of antigen production in the cell, preferably more efficient than a composition containing a corresponding unmodified polynucleotide encoding the same antigen. Increased antigen production may be demonstrated by increased cell transfection (i.e., the percentage of cells transfected with the NAV), increased protein translation from the polynucleotide, decreased nucleic acid degradation (as demonstrated, e.g., by increased duration of protein translation from a modified polynucleotide), or altered innate immune response of the host cell.

Aspects of the invention are directed to methods of inducing in vivo translation of a polypeptide antigen in a mammalian subject in need thereof. Therein, an effective amount of a NAV composition containing a polynucleotide that has at least one structural or chemical modification and a translatable region encoding the polypeptide (e.g., antigen or immunogen) is administered to the subject using the delivery methods described herein. The polynucleotide is provided in an amount and under other conditions such that the polynucleotide is translated in the cell. The cell in which the polynucleotide is localized, or the tissue in which the cell is present, may be targeted with one or more than one rounds of NAV administration.

In certain embodiments, the administered NAVs comprising polynucleotides directs production of one or more polypeptides that provide a functional immune system-related activity which is substantially absent in the cell, tissue or organism in which the polypeptide is translated. For example, the missing functional activity may be enzymatic, structural, or gene regulatory in nature. In related embodiments, the administered polynucleotides directs production of one or more polypeptides that increases (e.g., synergistically) a functional activity related to the immune system which is present but substantially deficient in the cell in which the polypeptide is translated.

Additionally, the polypeptide antagonizes, directly or indirectly, the activity of a biological moiety present in, on the surface of, or secreted from the cell. Examples of antagonized biological moieties include lipids (e.g., cholesterol), a lipoprotein (e.g., low density lipoprotein), a nucleic acid, a carbohydrate, a protein toxin such as shiga and tetanus toxins, or a small molecule toxin such as botulinum, cholera, and diphtheria toxins. Additionally, the antagonized biological molecule may be an endogenous protein that exhibits an undesirable activity, such as a cytotoxic or cytostatic activity.

The proteins described herein may be engineered for localization within the cell, potentially within a specific compartment such as the cytoplasms or nucleus, or are engineered for secretion from the cell or translocation to the plasma membrane of the cell.

In some embodiments, polynucleotides of the NAVs and their encoded polypeptides in accordance with the present invention may be used for treatment of any of a variety of diseases, disorders, and/or conditions, including but not limited to viral infections (e.g., influenza, HIV, HCV, RSV), parasitic infentions or bacterial infections.

The subject to whom the therapeutic agent may be administered suffers from or may be at risk of developing a disease, disorder, or deleterious condition. Provided are methods of identifying, diagnosing, and classifying subjects on these bases, which may include clinical diagnosis, biomarker levels, genome-wide association studies (GWAS), and other methods known in the art.

The agents can be administered simultaneously, for example in a combined unit dose (e.g., providing simultaneous delivery of both agents). The agents can also be administered at a specified time interval, such as, but not limited to, an interval of minutes, hours, days or weeks. Generally, the agents may be concurrently bioavailable, e.g., detectable, in the subject. In some embodiments, the agents may be administered essentially simultaneously, for example two unit dosages administered at the same time, or a combined unit dosage of the two agents. In other embodiments, the agents may be delivered in separate unit dosages. The agents may be administered in any order, or as one or more preparations that includes two or more agents. In a preferred embodiment, at least one administration of one of the agents, e.g., the first agent, may be made within minutes, one, two, three, or four hours, or even within one or two days of the other agent, e.g., the second agent. In some embodiments, combinations can achieve synergistic results, e.g., greater than additive results, e.g., at least 25, 50, 75, 100, 200, 300, 400, or 500% greater than additive results.

Modulation of the Immune Response

Activation of the Immune Response

According to the present invention, the NAVs comprising the polynucleotides disclosed herein, e.g., comprising RNA polynucleotides, may act as a single composition as a vaccine. As used herein, a “vaccine” refers to a composition, for example, a substance or preparation that stimulates, induces, causes or improves immunity in an organism, e.g., an animal organism, for example, a mammalian organism (e.g., a human.) Preferably, a vaccine provides immunity against one or more diseases or disorders in the organism, including prophylactic and/or therapeutic immunity. Exemplary vaccines includes one or more agents that resembles an infectious agent, e.g., a disease-causing microorganism, and can be made, for example, from live, attenuated, modified, weakened or killed forms of disease-causing microorganisms, or antigens derived therefrom, including combinations of antigenic components. In exemplary embodiments, a vaccine stimulates, induces causes or improves immunity in an organism or causes or mimics infection in the organism without inducing any disease or disorder. A vaccine introduces an antigen into the tissues, extracellular space or cells of a subject and elicits an immune response, thereby protecting the subject from a particular disease or pathogen infection. The polynucleotides of the present invention may encode an antigen and when the polynucleotides are expressed in cells, a desired immune reponse is achieved.

NAVs may be administered prophylactically or therapeutically as part of an active immunization scheme to healthy individuals or early in infection during the incubation phase or during active infection after onset of symptoms.

The NAVs of the present invention may also be administered as a second line treatment after the standard first line treatments such as antibiotics and antivirals have failed to induce passive immunity. In this regard, the NAVs of the present invention are useful in settings where resistance to first line treatments has developed and disease persists and induces chronic disease.

NAVs may be administered as part of a treatment regimen for latent bacterial infections, such as MRSA or Clostridium infections. In this embodiment, one or more polynucleotides are administered which ultimately produce proteins which result in the removal or alterations of the protective shield surrounding a bacterium making the bacterium more susceptible to antibiotic treatement.

In one embodiment, a polynucleotide encoding one or several generic or patient-specific antibiotic resistance genes is administered to a patient, e.g. NDM-1. The polunucleotide is then translated to produce the enzyme in vivo. This production may raise an antibody-mediated immune response to the secreted and/or the intracellular enzyme that neutralized the antibiotic resistance and provides the bacteria susceptibal to the clearance by available antibiotics again. Given the broad range of mutantions and variants in antibiotic resistance genes, it would be possible to sequence the specific bacteria genes hosted by the patients and design the exact vaccine for the specific variant in the infected patient.

The use of RNA in or as a vaccine overcomes the disadvantages of conventional genetic vaccination involving incorporating DNA into cells in terms of safeness, feasibility, applicability, and effectiveness to generate immune responses. RNA molecules are considered to be significantly safer than DNA vaccines, as RNAs are more easily degraded. They are cleared quickly out of the organism and cannot integrate into the genome and influence the cell's gene expression in an uncontrollable manner. It is also less likely for RNA vaccines to cause severe side effects like the generation of autoimmune disease or anti-DNA antibodies (Bringmann A. et al., Journal of Biomedicine and Biotechnology (2010), vol. 2010, article ID623687). Transfetion with RNA requires only insertion into the cell's cytoplasm, which is easier to achieve than into the nucleus. Howerver, RNA is susceptible to RNase degradation and other natural decomposition in the cytoplasm of cells.

Various attempts to increase the stability and shelf life of RNA vaccines. US 2005/0032730 to Von Der Mulbe et al. discloses improving the stability of mRNA vaccine compositions by increasing G(guanosine)/C(cytosine) content of the mRNA molecules. U.S. Pat. No. 5,580,859 to Felgner et al. teaches incorporating polynucleotide sequences coding for regulatory proteins that binds to and regulates the stabilities of mRNA. While not wishing to be bound by theory, it is believed that the polynucleotides vaccines (NAVs) of the invention will result in improved stability and therapeutic efficacy due at least in part to the specificity, purity and selectivity of the construct designs.

Additionally, certain modified nucleosides, or combinations thereof, when introduced into the polynucleotides of the NAVs of the invention will activate the innate immune response. Such activating molecules are useful as adjuvants when combined with polypeptides and/or other vaccines. In certain embodiments, the activating molecules contain a translatable region which encodes for a polypeptide sequence useful as a vaccine, thus providing the ability to be a self-adjuvant.

In one embodiment, the polynucleotides of the NAVs of the present invention may be used in the prevention, treatment and diagnosis of diseases and physical disturbances caused by infectious agents. The polynucleotide of the present invention may encode at least one polypeptide of interest (antigen) and may be provided to an individual in order to stimulate the immune system to protect against the disease-causing agents. As a non-limiting example, the biological activity and/or effect from an antigen or infectious agent may be inhibited and/or abolished by providing one or more polynucleotides which have the ability to bind and neutralize the antigen and/or infectious agent.

As a non-limiting example, the polynucleotides encoding an immunogen may be delivered to cells to trigger multiple innate response pathways (see International Pub. No. WO2012006377 and US Patent Publication No. US20130177639; herein incorporated by reference in its entirety). As another non-limiting example, the polynucleotides of the NAVs of the present invention encoding an immunogen may be delivered to a vertebrate in a dose amount large enough to be immunogenic to the vertebrate (see International Pub. No. WO2012006372 and WO2012006369 and US Publication No. US20130149375 and US20130177640; the contents of each of which are herein incorporated by reference in their entirety).

A non-limiting list of infectious diseases that the polynucleotide vaccines may treat includes, viral infectious diseases such as AIDS (HIV), HIV resulting in mycobacterial infection, AIDS related Cacheixa, AIDS related Cytomegalovirus infection, HIV-associated nephropathy, Lipodystrophy, AID related cryptococcal meningitis, AIDS related neutropaenia, Pneumocysitis jiroveci (Pneumocystis carinii) infections, AID related toxoplasmosis, hepatitis A, B, C, D or E, herpes, herpes zoster (chicken pox), German measles (rubella virus), yellow fever, dengue fever etc. (flavi viruses), flu (influenza viruses), haemorrhagic infectious diseases (Marburg or Ebola viruses), bacterial infectious diseases such as Legionnaires' disease (Legionella), gastric ulcer (Helicobacter), cholera (Vibrio), E. coli infections, staphylococcal infections, salmonella infections or streptococcal infections, tetanus (Clostridium tetani), protozoan infectious diseases (malaria, sleeping sickness, leishmaniasis, toxoplasmosis, i.e. infections caused by plasmodium, trypanosomes, leishmania and toxoplasma), diphtheria, leprosy, measles, pertussis, rabies, tetanus, tuberculosis, typhoid, varicella, diarrheal infections such as Amoebiasis, Clostridium difficile-associated diarrhea (CDAD), Cryptosporidiosis, Giardiasis, Cyclosporiasis and Rotaviral gastroenteritis, encephalitis such as Japanese encephalitis, Wester equine encephalitis and Tick-borne encephalitis (TBE), fungal skin diseases such as candidiasis, onychomycosis, Tinea captis/scal ringworm, Tinea corporis/body ringworm, Tinea cruris/jock itch, sporotrichosis and Tinea pedis/Athlete's foot, Meningitis such as Haemophilus influenza type b (Hib), Meningitis, viral, meningococcal infections and pneumococcal infection, neglected tropical diseases such as Argentine haemorrhagic fever, Leishmaniasis, Nematode/roundworm infections, Ross river virus infection and West Nile virus (WNV) disease, Non-HIV STDs such as Trichomoniasis, Human papillomavirus (HPV) infections, sexually transmitted chlamydial diseases, Chancroid and Syphilis, Non-septic bacterial infections such as cellulitis, lyme disease, MRSA infection, pseudomonas, staphylococcal infections, Boutonneuse fever, Leptospirosis, Rheumatic fever, Botulism, Rickettsial disease and Mastoiditis, parasitic infections such as Cysticercosis, Echinococcosis, Trematode/Fluke infections, Trichinellosis, Babesiosis, Hypodermyiasis, Diphyllobothriasis and Trypanosomiasis, respiratory infections such as adenovirus infection, aspergillosis infections, avian (H5N1) influenza, influenza, RSV infections, severe acute respiratory syndrome (SARS), sinusitis, Legionellosis, Coccidioidomycosis and swine (H1N1) influenza, sepsis such as bacteraemia, sepsis/septic shock, sepsis in premature infants, urinary tract infection such as vaginal infections (bacterial), vaginal infections (fungal) and gonococcal infection, viral skin diseases such as B19 parvovirus infections, warts, genital herpes, orofacial herpes, shingles, inner ear infections, fetal cytomegalovirus syndrome, foodborn illnesses such as brucellosis (Brucella species), Clostridium perfringens (Epsilon toxin), E. Coli O157:H7 (Escherichia coli), Salmonellosis (Salmonella species), Shingellosis (Shingella), Vibriosis and Listeriosis, bioterrorism and potential epidemic diseases such as Ebola haemorrhagic fever, Lassa fever, Marburg haemorrhagic fever, plague, Anthrax Nipah virus disease, Hanta virus, Smallpox, Glanders (Burkholderia mallei), Melioidosis (Burkholderia pseudomallei), Psittacosis (Chlamydia psittaci), Q fever (Coxiella burnetii), Tularemia (Fancisella tularensis), rubella, mumps and polio.

NAVs of the present invention may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non-limiting example, the NAVs of the present invention may be utilized to treat and/or prevent influenza infection, i.e. diseases and conditions related to influenza virus infection (seasonal and pandemic).

Symptoms of the influenza infection include dry cough, fever, chills, myalgias progressing to respiratory failure and the risk of secondary bacterial infections (e.g., MRSA). Seasonal influenza is ubiquitous and consists of three principal strains (A [H1N1], A [H3N2], and B), which are covered by the annual vaccine. Pandemic flu occurs because the viruses' unique reassortment ability allowing antigenic shift as well as transfer between avian and swine flu strains. One emerging concern in Southeast Asia is the pandemic potential of several new strains. Such pandemic outbreaks have a high mortality rate with few available treatments. Anti-virals only provide symptomatic relief and must be given in the first 48 hours.

The NAVs of the present invention have superior properties in that they produce much larger antibody titers, produce responses early than commercially available anti-virals and may be administered after the critical 48 hour period while retaining efficacy.

While not wishing to be bound by theory, the inventors hypothesize that the NAVs of the invention, as mRNA polynucleotides, are better designed to produce the appropriate protein conformation on translation as the NAVs co-opt natural cellular machinery. Unlike traditional vaccines which are manufactured ex vivo and may trigger unwanted cellular responses, the NAVs are presented to the cellular system in a more native fashion. Adding to the superior effects may also involve the formulations utilized which may neither serve to shield nor traffic the NAVs. According to the present invention, NAVs represent a tailored active vaccine that not only can prevent infection but can limit transmission of influenza.

In some embodiments, the NAVs may be used to prevent pandemic influenza by reacting to emerging new strains with the very rapid NAV-based vaccine production process. In some embodiments, new NAV for treating or prophylactically preventing influenza outbreaks, including for emerging strains (e.g., H10N8), may be produced in less than six weeks, from the time of antigen identification to available vaccine.

In some embodiments a single injection of a single antigen encoding NAV polynucleotide may provide protection for an entire flu season.

The polynucleotides of the NAVs of the invention are not self-replicating RNA. Self-replicating RNA have been described, for instance in US Pub. No. US20110300205 and International Pub. No. WO2011005799 and WO2013055905, the contents of each of which are herein incorporated by reference in their entirety.

In one embodiment, the polynucleotides of the NAVs of the invention may encode amphipathic and/or immunogenic amphipathic peptides.

In on embodiment, a formulation of the polynucleotides of the NAVs of the invention may further comprise an amphipathic and/or immunogenic amphipathic peptide. As a non-limiting example, the polynucleotides comprising an amphipathic and/or immunogenic amphipathic peptide may be formulated as described in US. Pub. No. US20110250237 and International Pub. Nos. WO2010009277 and WO2010009065; each of which is herein incorporated by reference in their entirety.

In one embodiment, the polynucleotides of the NAVs of the invention may be immunostimultory. As a non-limiting example, the polynucleotides may encode all or a part of a positive-sense or a negative-sense stranded RNA virus genome (see International Pub No. WO2012092569 and US Pub No. US20120177701, each of which is herein incorporated by reference in their entirety). In another non-limiting example, the immunostimultory polynucleotides of the present invention may be formulated with an excipient for administration as described herein and/or known in the art (see International Pub No. WO2012068295 and US Pub No. US20120213812, each of which is herein incorporated by reference in their entirety). The polynucleotides may further comprise a sequence region encoding a cytokine that promotes the immune response, such as a monokine, lymphokine, interleukin or chemokine, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, INF-α, INF-γ, GM-CFS, LT-α, or growth factors such as hGH.

In one embodiment, the response of the vaccine formulated by the methods described herein may be enhanced by the addition of various compounds to induce the therapeutic effect. As a non-limiting example, the vaccine formulation may include a MHC II binding peptide or a peptide having a similar sequence to a MHC II binding peptide (see International Pub Nos. WO2012027365, WO2011031298 and US Pub No. US20120070493, US20110110965, each of which is herein incorporated by reference in their entirety). As another example, the vaccine formulations may comprise modified nicotinic compounds which may generate an antibody response to nicotine residue in a subject (see International Pub No. WO2012061717 and US Pub No. US20120114677, each of which is herein incorporated by reference in their entirety).

In one embodiment, the effective amount of the polynucleotides of the NAVs of the invention provided to a cell, a tissue or a subject may be enough for immune prophylaxis.

In one embodiment, the polynucleotides of the NAVs of the invention may be administrated with other prophylactic or therapeutic compounds. As a non-limiting example, the prophylactic or therapeutic compound may be an adjuvant or a booster. As used herein, when referring to a prophylactic composition, such as a vaccine, the term “booster” refers to an extra administration of the prophylactic composition. A booster (or booster vaccine) may be given after an earlier administration of the prophylactic composition. The time of administration between the intial administration of the prophylactic composition and the booster may be, but is not limited to, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 25 years, 30 years, 35 years, 40 years, 45 years, 50 years, 55 years, 60 years, 65 years, 70 years, 75 years, 80 years, 85 years, 90 years, 95 years or more than 99 years.

In one embodiment, the polynucleotides of the NAVs of the invention may be administered intranasally similar to the administration of live vaccines. In another aspect the polynucleotide may be administered intramuscularly or intradermally similarly to the administration of inactivated vaccines known in the art.

In one embodiment, the NAVs of the invention may be used to protect against and/or prevent the transmission of an emerging or engineered threat which may be known or unknown.

In another embodiment, the NAVs may be formulated by the methods described herein. In one aspect, the formulation may comprise a NAV or polynucleotide which can can have a therapetutic and/or prophylactic effect on more than one disease, disorder or condition. As a non-limiting example, the formulation may comprise polynucleotides encoding an antigen, including but not limited to a protein from an infectious agent such as a viral protein, a parasite protein or a bacterial protein.

In addition, the NAV antibodies of the present invention may be used for research in many applications, such as, but not limited to, identifying and locating intracellular and extracellular proteins, protein interaction, signal pathways and cell biology.

In another embodiment, the NAV may be used in to reduce the risk or inhibit the infection of influenza viruses such as, but not limited to, the highly pathogenic avian influenza virus (such as, but not limited to, H5N1 subtype) infection and human influenza virs (such as, but not limited to, H1N1 subtype and H3N2 subtype) infection. The polynucleotide described herein which may encode any of the protein sequences described in U.S. Pat. No. 8,470,771, the contents of which are herein incorporated by reference in its entirety, may be used in the treatment or to reduce the risk of an influenza infection.

In one embodiment, the NAV may be used to as a vaccine or modulating the immune response against a protein produced by a parasite. Bergmann-Leitner et al. in U.S. Pat. No. 8,470,560, the contents of which are herein incorporated by reference in its entirety, describe a DNA vaccine against the circumsporozoite protein (CSP) of malaria parasites. As a non-limiting example, the polynucleotide may encode the CR2 binding motif of C3d and may be used a vaccine or therapeutic to modulate the immune system against the CSP of malaria parasites.

In one embodiment, the NAV may be used as a vaccine and may further comprise an adjuvant which may enable the vaccine to elicit a higher immune response. As a non-limiting example, the adjuvant could be a sub-micron oil-in-water emulsion which can elicit a higher immune response in human pediatric populations (see e.g., the adjuvanted vaccines described in US Patent Publication No. US20120027813 and U.S. Pat. No. 8,506,966, the contents of each of which are herein incorporated by reference in its entirety).

II. Infectious Agents and Antigens

NAVs of the present invention may be used to protect, treat or cure infection arising from contact with an infectious agent, e.g., microorganism. Infectious agents include bacteria, viruses, fungi, protozoa and parasites.

A. Managing Infection

In one embodiment, provided are methods for treating or preventing a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial or viral infection, or a symptom thereof, in a subject, by administering a NAV comprising one or more polynucleotide encoding an anti-microbial polypeptide. The administration may be in combination with an anti-microbial agent (e.g., an anti-bacterial agent), e.g., an anti-microbial polypeptide or a small molecule anti-microbial compound described herein. The anti-microbial agents include, but are not limited to, anti-bacterial agents, anti-viral agents, anti-fungal agents, anti-protozoal agents, anti-parasitic agents, and anti-prion agents.

Conditions Associated with Bacterial Infection

Diseases, disorders, or conditions which may be associated with bacterial infections which may be treated using the NAVs of the invention include, but are not limited to one or more of the following: abscesses, actinomycosis, acute prostatitis, Aeromonas hydrophila, annual ryegrass toxicity, anthrax, bacillary peliosis, bacteremia, bacterial gastroenteritis, bacterial meningitis, bacterial pneumonia, bacterial vaginosis, bacterium-related cutaneous conditions, bartonellosis, BCG-oma, botryomycosis, botulism, Brazilian purpuric fever, Brodie abscess, brucellosis, Buruli ulcer, campylobacteriosis, caries, Carrion's disease, cat scratch disease, cellulitis, chlamydia infection, cholera, chronic bacterial pro statitis, chronic recurrent multifocal osteomyelitis, clostridial necrotizing enteritis, combined periodontic-endodontic lesions, contagious bovine pleuropneumonia, diphtheria, diphtheritic stomatitis, ehrlichiosis, erysipelas, piglottitis, erysipelas, Fitz-Hugh-urtis syndrome, flea-borne spotted fever, foot rot (infectious pododermatitis), Garre's sclerosing osteomyelitis, Gonorrhea, Granuloma inguinale, human granulocytic anaplasmosis, human monocytotropic ehrlichiosis, hundred days' cough, impetigo, late congenital syphilitic oculopathy, legionellosis, Lemierre's syndrome, leprosy (Hansen's Disease), leptospirosis, listeriosis, Lyme disease, lymphadenitis, melioidosis, meningococcal disease, meningococcal septicaemia, methicillin-resistant Staphylococcus aureus (MRSA) infection, Mycobacterium avium-intracellulare (MAI), mycoplasma pneumonia, necrotizing fasciitis, nocardiosis, noma (cancrum oris or gangrenous stomatitis), omphalitis, orbital cellulitis, osteomyelitis, overwhelming post-splenectomy infection (OPSI), ovine brucellosis, pasteurellosis, periorbital cellulitis, pertussis (whooping cough), plague, pneumococcal pneumonia, Pott disease, proctitis, pseudomonas infection, psittacosis, pyaemia, pyomyositis, Q fever, relapsing fever (typhinia), rheumatic fever, Rocky Mountain spotted fever (RMSF), rickettsiosis, salmonellosis, scarlet fever, sepsis, serratia infection, shigellosis, southern tick-associated rash illness, staphylococcal scalded skin syndrome, streptococcal pharyngitis, swimming pool granuloma, swine brucellosis, syphilis, syphilitic aortitis, tetanus, toxic shock syndrome (TSS), trachoma, trench fever, tropical ulcer, tuberculosis, tularemia, typhoid fever, typhus, urogenital tuberculosis, urinary tract infections, vancomycin-resistant Staphylococcus aureus infection, Waterhouse-Friderichsen syndrome, pseudotuberculosis (Yersinia) disease, and yersiniosis

Bacterial Pathogens

The bacterium described herein can be a Gram-positive bacterium or a Gram-negative bacterium. Bacterial pathogens include, but are not limited to, Acinetobacter baumannii, Bacillus anthracis, Bacillus subtilis, Bordetella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, coagulase Negative Staphylococcus, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, enterotoxigenic Escherichia coli (ETEC), enteropathogenic E. coli, E. coli O157:H7, Enterobacter sp., Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Listeria monocytogenes, Moraxella catarralis, Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitides, Preteus mirabilis, Proteus sps., Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneri, Shigella sonnei, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Treponema pallidum, Vibrio cholerae, and Yersinia pestis.

Bacterial pathogens may also include bacteria that cause resistant bacterial infections, for example, clindamycin-resistant Clostridium difficile, fluoroquinolon-resistant Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Enterococcus faecalis, multidrug-resistant Enterococcus faecium, multidrug-resistance Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and vancomycin-resistant Staphylococcus aureus (VRSA).

Antibiotic Combinations

In one embodiment, the NAVs of the present invention, e.g., NAVs comprising one or more antigen-encoding polynucleotides of the present invention, may be administered in conjunction with one or more antibiotics.

Antibacterial Agents

Anti-bacterial agents include, but are not limited to, aminoglycosides (e.g., amikacin (AMIKIN®), gentamicin (GARAMYCIN®), kanamycin (KANTREX®), neomycin (MYCIFRADIN®), netilmicin (NETROMYCIN®), tobramycin (NEBCIN®), Paromomycin (HUMATIN®)), ansamycins (e.g., geldanamycin, herbimycin), carbacephem (e.g., loracarbef (LORABID®), Carbapenems (e.g., ertapenem (INVANZ®), doripenem (DORIBAX®), imipenem/cilastatin (PRIMAXIN®), meropenem (MERREM®), cephalosporins (first generation) (e.g., cefadroxil (DURICEF®), cefazolin (ANCEF®), cefalotin or cefalothin (KEFLIN®), cefalexin (KEFLEX®), cephalosporins (second generation) (e.g., cefaclor (CECLOR®), cefamandole (MANDOL®), cefoxitin (MEFOXIN®), cefprozil (CEFZIL®), cefuroxime (CEFTIN®, ZINNAT®)), cephalosporins (third generation) (e.g., cefixime (SUPRAX®), cefdinir (OMNICEF®, CEFDIEL®), cefditoren (SPECTRACEF®), cefoperazone (CEFOBID®), cefotaxime (CLAFORAN®), cefpodoxime (VANTIN®), ceftazidime (FORTAZ®), ceftibuten (CEDAX®), ceftizoxime (CEFIZOX®), ceftriaxone (ROCEPHIN®)), cephalosporins (fourth generation) (e.g., cefepime (MAXIPIME®)), cephalosporins (fifth generation) (e.g., ceftobiprole (ZEFTERA®)), glycopeptides (e.g., teicoplanin (TARGOCID®), vancomycin (VANCOCIN®), telavancin (VIBATIV®)), lincosamides (e.g., clindamycin (CLEOCIN®), lincomycin (LINCOCIN®)), lipopeptide (e.g., daptomycin (CUBICIN®)), macrolides (e.g., azithromycin (ZITHROMAX®, SUMAMED®, ZITROCIN®), clarithromycin (BIAXIN®), dirithromycin (DYNABAC®), erythromycin (ERYTHOCIN®, ERYTHROPED®), roxithromycin, troleandomycin (TAO®), telithromycin (KETEK®), spectinomycin (TROBICIN®)), monobactams (e.g., aztreonam (AZACTAM®)), nitrofurans (e.g., furazolidone (FUROXONE®), nitrofurantoin (MACRODANTIN®, MACROBID®)), penicillins (e.g., amoxicillin (NOVAMOX®, AMOXIL®), ampicillin (PRINCIPEN®), azlocillin, carbenicillin (GEOCILLIN®), cloxacillin (TEGOPEN®), dicloxacillin (DYNAPEN®), flucloxacillin (FLOXAPEN®), mezlocillin (MEZLIN®), methicillin (STAPHCILLIN®), nafcillin (UNIPEN®), oxacillin (PROSTAPHLIN®), penicillin G (PENTIDS®), penicillin V (PEN-VEE-K®), piperacillin (PIPRACIL®), temocillin (NEGABAN®), ticarcillin (TICAR®)), penicillin combinations (e.g., amoxicillin/clavulanate (AUGMENTIN®), ampicillin/sulbactam (UNASYN®), piperacillin/tazobactam (ZOSYN®), ticarcillin/clavulanate (TIMENTIN®)), polypeptides (e.g., bacitracin, colistin (COLY-MYCIN-S®), polymyxin B, quinolones (e.g., ciprofloxacin (CIPRO®, CIPROXIN®, CIPROBAY®), enoxacin (PENETREX®), gatifloxacin (TEQUIN®), levofloxacin (LEVAQUIN®), lomefloxacin (MAXAQUIN®), moxifloxacin (AVELOX®), nalidixic acid (NEGGRAM®), norfloxacin (NOROXIN®), ofloxacin (FLOXIN®, OCUFLOX®), trovafloxacin (TROVAN®), grepafloxacin (RAXAR®), sparfloxacin (ZAGAM®), temafloxacin (OMNIFLOX®)), sulfonamides (e.g., mafenide (SULFAMYLON®), sulfonamidochrysoidine (PRONTOSIL®), sulfacetamide (SULAMYD®, BLEPH-10®), sulfadiazine (MICRO-SULFON®), silver sulfadiazine (SILVADENE®), sulfamethizole (THIOSULFIL FORTE®), sulfamethoxazole (GANTANOL®), sulfanilimide, sulfasalazine (AZULFIDINE®), sulfisoxazole (GANTRISIN®), trimethoprim (PROLOPRIM®), TRIMPEX®), trimethoprim-sulfamethoxazole (co-trimoxazole) (TMP-SMX) (BACTRIM®, SEPTRA®)), tetracyclines (e.g., demeclocycline (DECLOMYCIN®), doxycycline (VIBRAMYCIN®), minocycline (MINOCIN®), oxytetracycline (TERRAMYCIN®), tetracycline (SUMYCIN®, ACHROMYCIN® V, STECLIN®)), drugs against mycobacteria (e.g., clofazimine (LAMPRENE®), dapsone (AVLOSULFON®), capreomycin (CAPASTAT®), cycloserine (SEROMYCIN®), ethambutol (MYAMBUTOL®), ethionamide (TRECATOR®), isoniazid (I.N.H.®), pyrazinamide (ALDINAMIDE®), rifampin (RIFADIN®, RIMACTANE®), rifabutin (MYCOBUTIN®), rifapentine (PRIFTIN®), streptomycin), and others (e.g., arsphenamine (SALVARSAN®), chloramphenicol (CHLOROMYCETIN®), fosfomycin (MONUROL®), fusidic acid (FUCIDIN®), linezolid (ZYVOX®), metronidazole (FLAGYL®), mupirocin (BACTROBAN®), platensimycin, quinupristin/dalfopristin (SYNERCID®), rifaximin (XIFAXAN®), thiamphenicol, tigecycline (TIGACYL®), tinidazole (TINDAMAX®, FASIGYN®)).

Conditions Associated with Viral Infection

In another embodiment, provided are methods for treating or preventing a viral infection and/or a disease, disorder, or condition associated with a viral infection, or a symptom thereof, in a subject, by administering aRNAV comprising one or more polynucleotides encoding an anti-viral polypeptide, e.g., an anti-viral polypeptide described herein in combination with an anti-viral agent, e.g., an anti-viral polypeptide or a small molecule anti-viral agent described herein.

Diseases, disorders, or conditions associated with viral infections which may be treated using the NAVs of the invention include, but are not limited to, acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic epithelial lesions (e.g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, bronchiolitis, pneumonia, influenza-like syndrome, severe bronchiolitis with pneumonia, German measles, congenital rubella, Varicella, and herpes zoster.

Viral Pathogens

Examples of viral infectious agents include, but are not limited to, adenovirus; Herpes simplex, type 1; Herpes simplex, type 2; encephalitis virus, papillomavirus, Varicella-zoster virus; Epstein-barr virus; Human cytomegalovirus; Human herpesvirus, type 8; Human papillomavirus; BK virus; JC virus; Smallpox; polio virus, Hepatitis B virus; Human bocavirus; Parvovirus B19; Human astrovirus; Norwalk virus; coxsackievirus; hepatitis A virus; poliovirus; rhinovirus; Severe acute respiratory syndrome virus; Hepatitis C virus; yellow fever virus; dengue virus; West Nile virus; Rubella virus; Hepatitis E virus; Human immunodeficiency virus (HIV); Influenza virus, type A or B; Guanarito virus; Junin virus; Lassa virus; Machupo virus; Sabia virus; Crimean-Congo hemorrhagic fever virus; Ebola virus; Marburg virus; Measles virus; Mumps virus; Parainfluenza virus; Respiratory syncytial virus; Human metapneumovirus; Hendra virus; Nipah virus; Rabies virus; Hepatitis D; Rotavirus; Orbivirus; Coltivirus; Hantavirus, Middle East Respiratory Coronavirus; Chikungunya virus or Banna virus.

Viral pathogens may also include viruses that cause resistant viral infections.

Antiviral Agents

Exemplary anti-viral agents include, but are not limited to, abacavir (ZIAGEN®), abacavir/lamivudine/zidovudine (Trizivir®), aciclovir or acyclovir (CYCLOVIR®, HERPEX®, ACIVIR®, ACIVIRAX®, ZOVIRAX®, ZOVIR®), adefovir (Preveon®, Hepsera®), amantadine (SYMMETREL®), amprenavir (AGENERASE®), ampligen, arbidol, atazanavir (REYATAZ®), boceprevir, cidofovir, darunavir (PREZISTA®), delavirdine (RESCRIPTOR®), didanosine (VIDEX®), docosanol (ABREVA®), edoxudine, efavirenz (SUSTIVA®, STOCRIN®), emtricitabine (EMTRIVA®), emtricitabine/tenofovir/efavirenz (ATRIPLA®), enfuvirtide (FUZEON®), entecavir (BARACLUDE®, ENNAVIR®), famciclovir (FAMVIR®), fomivirsen (VITRAVENE®), fosamprenavir (LEXIVA®, TELZIR®), foscarnet (FOSCAVIR®), fosfonet, ganciclovir (CYTOVENE®, CYMEVENE®, VITRASERT®), GS 9137 (ELVITEGRAVIR®), imiquimod (ALDARA®, ZYCLARA®, BESELNA®), indinavir (CRIXIVAN®), inosine, inosine pranobex (IMUNOVIR®), interferon type I, interferon type II, interferon type III, kutapressin (NEXAVIR®), lamivudine (ZEFFIX®, HEPTOVIR®, EPIVIR®), lamivudine/zidovudine (COMBIVIR®), lopinavir, loviride, maraviroc (SELZENTRY®, CELSENTRI®), methisazone, MK-2048, moroxydine, nelfinavir (VIRACEPT®), nevirapine (VIRAMUNE®), oseltamivir (TAMIFLU®), peginterferon alfa-2a (PEGASYS®), penciclovir (DENAVIR®), peramivir, pleconaril, podophyllotoxin (CONDYLOX®), raltegravir (ISENTRESS®), ribavirin (COPEGUs®, REBETOL®, RIBASPHERE®, VILONA® AND VIRAZOLE®), rimantadine (FLUMADINE®), ritonavir (NORVIR®), pyramidine, saquinavir (INVIRASE®, FORTOVASE®), stavudine, tea tree oil (melaleuca oil), tenofovir (VIREAD®), tenofovir/emtricitabine (TRUVADA®), tipranavir (APTIVUS®), trifluridine (VIROPTIC®), tromantadine (VIRU-MERZ®), valaciclovir (VALTREX®), valganciclovir (VALCYTE®), vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir (RELENZA®), and zidovudine (azidothymidine (AZT), RETROVIR®, RETROVIS®).

Conditions Associated with Fungal Infections

Diseases, disorders, or conditions associated with fungal infections which may be treated using the NAVs of the invention include, but are not limited to, aspergilloses, blastomycosis, candidasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mycetomas, paracoccidioidomycosis, and tinea pedis. Furthermore, persons with immuno-deficiencies are particularly susceptible to disease by fungal genera such as Aspergillus, Candida, Cryptoccocus, Histoplasma, and Pneumocystis. Other fungi can attack eyes, nails, hair, and especially skin, the so-called dermatophytic fungi and keratinophilic fungi, and cause a variety of conditions, of which ringworms such as athlete's foot are common. Fungal spores are also a major cause of allergies, and a wide range of fungi from different taxonomic groups can evoke allergic reactions in some people.

Fungal Pathogens

Fungal pathogens include, but are not limited to, Ascomycota (e.g., Fusarium oxysporum, Pneumocystis jirovecii, Aspergillus spp., Coccidioides immitis/posadasii, Candida albicans), Basidiomycota (e.g., Filobasidiella neoformans, Trichosporon), Microsporidia (e.g., Encephalitozoon cuniculi, Enterocytozoon bieneusi), and Mucoromycotina (e.g., Mucor circinelloides, Rhizopus oryzae, Lichtheimia corymbifera).

Anti Fungal Agents

Exemplary anti-fungal agents include, but are not limited to, polyene antifungals (e.g., natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, hamycin), imidazole antifungals (e.g., miconazole (MICATIN®, DAKTARIN®), ketoconazole (NIZORAL®, FUNGORAL®, SEBIZOLE®), clotrimazole (LOTRIMIN®, LOTRIMIN® AF, CANESTEN®), econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole (ERTACZO®), sulconazole, tioconazole), triazole antifungals (e.g., albaconazole fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole), thiazole antifungals (e.g., abafungin), allylamines (e.g., terbinafine (LAMISIL®), naftifine (NAFTIN®), butenafine (LOTRIMIN® Ultra)), echinocandins (e.g., anidulafungin, caspofungin, micafungin), and others (e.g., polygodial, benzoic acid, ciclopirox, tolnaftate (TINACTIN®, DESENEX®, AFTATE®), undecylenic acid, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, sodium bicarbonate, allicin).

Conditions Associated with Protozoal Infection

Diseases, disorders, or conditions associated with protozoal infections which may be treated using the NAVs of the invention include, but are not limited to, amoebiasis, giardiasis, trichomoniasis, African Sleeping Sickness, American Sleeping Sickness, leishmaniasis (Kala-Azar), balantidiasis, toxoplasmosis, malaria, acanthamoeba keratitis, and babesiosis.

Protozoan Pathogens

Protozoal pathogens include, but are not limited to, Entamoeba histolytica, Giardia lambila, Trichomonas vaginalis, Trypanosoma brucei, T. cruzi, Leishmania donovani, Balantidium coli, Toxoplasma gondii, Plasmodium spp., and Babesia microti.

Anti-Protozoan Agents

Exemplary anti-protozoal agents include, but are not limited to, eflornithine, furazolidone (FUROXONE®, DEPENDAL-M®), melarsoprol, metronidazole (FLAGYL®), ornidazole, paromomycin sulfate (HUMATIN®), pentamidine, pyrimethamine (DARAPRIM®), and tinidazole (TINDAMAX®, FASIGYN®).

Conditions Associated with Parasitic Infection

Diseases, disorders, or conditions associated with parasitic infections which may be treated using the NAVs of the invention include, but are not limited to, acanthamoeba keratitis, amoebiasis, ascariasis, babesiosis, balantidiasis, baylisascariasis, chagas disease, clonorchiasis, cochliomyia, cryptosporidiosis, diphyllobothriasis, dracunculiasis, echinococcosis, elephantiasis, enterobiasis, fascioliasis, fasciolopsiasis, filariasis, giardiasis, gnathostomiasis, hymenolepiasis, isosporiasis, katayama fever, leishmaniasis, lyme disease, malaria, metagonimiasis, myiasis, onchocerciasis, pediculosis, scabies, schistosomiasis, sleeping sickness, strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis, and trichuriasis.

Parasitic Pathogens

Parasitic pathogens include, but are not limited to, Acanthamoeba, Anisakis, Ascaris lumbricoides, botfly, Balantidium coli, bedbug, Cestoda, chiggers, Cochliomyia hominivorax, Entamoeba histolytica, Fasciola hepatica, Giardia lamblia, hookworm, Leishmania, Linguatula serrata, liver fluke, Loa boa, Paragonimus, pinworm, Plasmodium falciparum, Schistosoma, Strongyloides stercoralis, mite, tapeworm, Toxoplasma gondii, Trypanosoma, whipworm, Wuchereria bancrofti.

Anti-Parasitic Agents

Exemplary anti-parasitic agents include, but are not limited to, antinematodes (e.g., mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin), anticestodes (e.g., niclosamide, praziquantel, albendazole), antitrematodes (e.g., praziquantel), antiamoebics (e.g., rifampin, amphotericin B), and antiprotozoals (e.g., melarsoprol, eflornithine, metronidazole, tinidazole).

B. Therapeutic Settings and/or Situations

NAVs of the present invention may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. Some applications of the NAVs of the invention are outlined in Table 1.

TABLE 1 Infectious Agents by prevalence and Medical Need Unmet Need (Infectious Agent Target) Short term benign Short term morbidity Short term mortality; Prevalence Long term sequelae but some treatment no treatment available Ubiquitous HPV, HCV, UTRIs Dengue, Chikungunya, seasonal and pandemic ETEC and GI bacteria influenza, MRSA and TB and S. Pneumo PNA At risk VZV, Lyme and Noroviruses, HEV, Klebsiella, Pseudomonas, populations Chlamydia, CMV, HIV and Rabies and C. difficile N. gonorrhea and N. meningitis HSV Rare disease — VEV toxin-mediated diseases, hantavirus, arborviruses such as JE, WNV and EEE Certain abbreviations include: HPV—Human Papillomavirus; HCV—Hepatitis C Virus; HEV—Human Enterovirus; MERS-CoV: Middle East Respiratory Syndrom Corona Virus; VZV—Varicella-zoster Virus; MRSA—Methicillin-resistant Staph areus; TB—tuberculosis; WNV—West Nile Virus; VEV—vesicular exanthema virus; EEE—Eastern equine encephalitis, JE—Japanese encephalitis, ETEC—Enterotoxigenic E. coli.

Influenza (Seasonal and Pandemic)

Symptoms of the flu include dry cough, fever, chills, myalgias progressing to respiratory failure and the risk of secondary bacterial infections (e.g., MRSA). Seasonal influenza is ubiquitous and consists of three principal strains (A [H1N1], A [H3N2], and B), which are covered by the annual vaccine. Pandemic flu occurs because the viruses' unique reassortment ability allowing antigenic shift as well as transfer between avian and swine flu strains. One emerging concern in Southeast Asia is the pandemic potential of several new strains. Such pandemic outbreaks have a high mortality rate with few available treatments. Anti-virals only provide symptomatic relief and must be given in the first 48 hours.

The NAVs of the present invention have superior properties in that they produce much larger antibody titers, produce responses early than commercially available anti-virals and may be administered after the critical 48 hour period while retaining efficacy.

While not wishing to be bound by theory, the inventors hypothesize that the NAVs of the invention, as mRNA polynucleotides, are better designed to produce the appropriate protein conformation on translation as the NAVs co-opt natural cellular machinery. Unlike tranditional vaccines which are manufactured ex vivo and may trigger unwanted cellular responses, the NAVs are presented to the cellular system in amore native fashion. Adding to the superior effects may also involve the formulations utilized which may enither serve to shield or traffic the NAVs.

According to the present invention, NAVs represent a tailored active vaccine that not only can prevent infection but can limit transmission of influenza.

In some embodiments, the NAVs may be used to prevent pandemic influenza by reacting to emerging new strains with the very rapid NAV-based vaccine production process. In some embodiments, new NAV for treating or prophylactically preventing influenza outbreaks, including for emerging strains (e.g., H7N9 and H10N8), may be produced in less than six weeks, from the time of antigen identification to available vaccine.

In some embodiments a single injection of a single antigen encoding NAV polynucleotide may provide protection for an entire flu season.

Influenza: Maintenance of Antigenic Memory

The NAV compositions of the present invention may also be used to maintain or restore antigenic memory in a subject or population as part of a vaccination plan.

With the speed and versatility of the NAV technology of the present invention, it is now possible to create a vaccination plan that spans both temporal and viral strain space.

In one embodiment, NAV compositions may be created which include polynucleotides that encode one or more flu year antigens. As used herein a flu year antigen is an antigen which is selected from a strain of influenza used as a component of a flu vaccine from a particular year. For example, the influenza A strain, A/Port Chalmers/1/1973(H3N2)-like virus, represents one strain component of the Northern Hemisphere vaccine from 1974-1975.

According to the present invention, a vaccination scheme or plan is developed which allows for not only ongoing vaccination in the current year but antigenic memory booster vaccinations across years, strains, or groups thereof to establish and maintain antigenic memory in a population. In this manner, a population is less likely to succumb to any pandemic or outbreak involving recurrence of older strains or the appearance of antigens from older strains.

Any combination of prior vaccine component strains utilized to create or design an antigenic memory booster vaccine is referred to here as a reference set.

In one embodiment, NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory across a time period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50 or more years.

In one embodiment, NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory for alternating historic years including every other year from the past vaccine component strains relative to a current year. In some embodiments the selection of the vaccine components can be from every 3^(rd), 4^(th), 5^(th), 6^(th), 7^(th), 8^(th), 9^(th), 10^(th) or more years.

In one embodiment, NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory over ten year periods.

In some embodiments NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory and are selected from a number of influenza type A strains as a first selection combined with a selection from a number of influenza type B strains or other strains listed herein. The number of selections of type A or type B may be independently, 1, 2, 1, 4, 5, 6, 7, 8, 9, 10 or more.

In all cases, the antigenic memory booster vaccine strains for antigen encoding in the NAVs may be selected from either the Northern or Southern hemisphere vaccine components independently.

In some embodiments, the NAV booster vaccine may be used in a population either once or periodically to create herd immunity. Such immunity is present when greater than 30% of a population is protected.

The components or strains of influenza which may be utilized in the antigenic memory booster vaccines include, but are not limited to, those in Tables 2-5.

TABLE 2 Influenza vaccine components by year additional Northern B-strain hemisphere H1N1 H3N2 B-strain for QIV 1974-1975 N/A A/Port Chalmers/1/ B/HongKong/05/ N/A 1973(H3N2)-like virus 1972-like virus 1975-1976 A/Scotland/840/ A/Port Chalmers/1/ B/HongKong/05/ N/A 74-like virus H1N1 1973(H3N2)-like virus 1972-like virus 1976-1977 N/A A/Victoria/3/ B/HongKong/05/ N/A 75(H3N2)-like virus 1972-like virus 1977-1978 N/A A/Victoria/3/ B/HongKong/05/ N/A 75(H3N2)-like virus 1972-like virus 1978-1979 A/USSR/90/ A/Texas/1/ B/HongKong/05/ N/A 77(H1N1)-like virus 77(H3N2)-like virus 1972-like virus 1979-1980 A/USSR/90/ A/Texas/1/ N/A N/A 77(H1N1)-like virus 77(H3N2)-like virus 1980-1981 A/Brazil/11/ A/Bangkok/01/1979 B/Singapore/222/ N/A 78(H1N1)-like virus (H3N2)-like virus 79-like virus 1981-1982 A/Brazil/11/ A/Bangkok/01/1979 B/Singapore/222/ N/A 78(H1N1)-like virus (H3N2)-like virus 79-like virus 1982-1983 A/Brazil/11/ A/Bangkok/01/1979 B/Singapore/222/ N/A 78(H1N1)-like virus (H3N2)-like virus 79-like virus 1983-1984 A/Brazil/11/ A/Philippines/2/ B/Singapore/222/ N/A 78(H1N1)-like virus 82(H3N2)-like virus 79-like virus 1984-1985 A/Chile/1/ A/Philippines/2/ B/USSR/100/ N/A 83(H1N1)-like virus 82(H3N2)-like virus 83-like virus 1985-1986 A/Chile/1/ A/Philippines/2/ B/USSR/100/ N/A 83(H1N1)-like virus 82(H3N2)-like virus 83-like virus 1986-1987 A/Chile/1/ A/Christchurch/4/ B/Ann Arbor/1/ N/A 83(H1N1)-like virus 1985(H3N2)-like virus 86-like virus and A/Mississippi/1/ 85(H3N2)-like virus 1987-1988 A/Singapore/6/1986 A/Leningrad/360/ N/A N/A (H1N1)-like virus 1986(H3N2)-like strain 1988-1989 A/Singapore/6/1986 A/Sichuan/02/ B/Beijing/1/ N/A (H1N1)-like virus 87(H3N2)-like virus 87-like rivus 1989-1990 A/Singapore/6/1986 A/Shanghai/11/ B/Yamagata/16/ N/A (H1N1)-like virus 87(H3N2)-like virus 88-like virus 1990-1991 A/Singapore/6/1986 A/Guizhou/54/ B/Yamagata/16/ N/A (H1N1)-like virus 89(H3N2)-like virus 88-like virus 1991-1992 A/Singapore/6/1986 A/Beijing/353/ B/Yamagata/16/ N/A (H1N1)-like virus 89(H3N2)-like virus 88-like virus 1992-1993 N/A A/Beijing/353/ B/Yamagata/16/ N/A 89(H3N2)-like virus 88-like virus 1993-1994 A/Singapore/6/1986 A/Beijing/32/ B/Panama/45/ N/A (H1N1)-like virus 92(H3N2)-like virus 90-like virus 1994-1995 A/Singapore/6/1986 A/Shangdong/9/ B/Panama/45/ N/A (H1N1)-like virus 93(H3N2)-like virus 90-like virus 1995-1996 A/Singapore/6/1986 A/Johannesburg/33/ B/Beijing/184/ N/A (H1N1)-like virus 94(H3N2)-like virus 93-like virus 1996-1997 A/Singapore/6/1986 A/Wuhan/359/ B/Beijing/184/ N/A (H1N1)-like virus 95(H3N2)-like virus 93-like virus 1997-1998 A/Bayern/7/ A/Wuhan/359/ B/Beijing/184/ N/A 95(H1N1)-like virus 95(H3N2)-like virus 93-like virus

TABLE 3 Influenza vaccine components by year-Southern Hemisphere additional Southern B-strain Hemisphere H1N1 H3N2 B-strain for QIV 1975 N/A A/Port Chalmers/1/ B/HongKong/05/ N/A 1973(H3N2)-like virus 1972-like virus 1976 A/Scotland/840/ A/Port Chalmers/1/ B/HongKong/05/ N/A 74-like virus (H1N1) 1973(H3N2)-like virus 1972-like virus 1977 N/A A/Victoria/3/ B/HongKong/05/ N/A 75(H3N2)-like virus 1972-like virus 1978 N/A A/Victoria/3/ B/HongKong/05/ N/A 75(H3N2)-like virus 1972-like virus 1979 A/USSR/90/ A/Texas/1/ B/HongKong/05/ N/A 77(H1N1)-like virus 77(H3N2)-like virus 1972-like virus 1980 A/USSR/90/ A/Texas/1/ N/A N/A 77(H1N1)-like virus 77(H3N2)-like virus 1981 A/Brazil/11/ A/Bangkok/01/1979 B/Singapore/222/ N/A 78(H1N1)-like virus (H3N2)-like virus 79-like virus 1982 A/Brazil/11/ A/Bangkok/01/1979 B/Singapore/222/ N/A 78(H1N1)-like virus (H3N2)-like virus 79-like virus 1983 A/Brazil/11/ A/Bangkok/01/1979 B/Singapore/222/ N/A 78(H1N1)-like virus (H3N2)-like virus 79-like virus 1984 A/Brazil/11/ A/Philippines/2/ B/Singapore/222/ N/A 78(H1N1)-like virus 82(H3N2)-like virus 79-like virus 1985 A/Chile/1/ A/Philippines/2/ B/USSR/100/ N/A 83(H1N1)-like virus 82(H3N2)-like virus 83-like virus 1986 A/Chile/1/ A/Philippines/2/ B/USSR/100/ N/A 83(H1N1)-like virus 82(H3N2)-like virus 83-like virus 1987 A/Chile/1/ A/Christchurch/4/ B/Ann Arbor/1/ N/A 83(H1N1)-like virus 1985(H3N2)-like virus 86-like virus and A/Mississippi/1/ 85(H3N2)-like virus 1988 A/Singapore/6/1986 A/Leningrad/360/ N/A N/A (H1N1)-like virus 1986(H3N2)-like virus 1989 A/Singapore/6/1986 A/Sichuan/02/ B/Beijing/1/ N/A (H1N1)-like virus 87(H3N2)-like virus 87-like virus 1990 A/Singapore/6/1986 A/Shanghai/11/ B/Yamagata/16/ N/A (H1N1)-like virus 87(H3N2)-like virus 88-like virus 1991 A/Singapore/6/1986 A/Guizhou/54/ B/Yamagata/16/ N/A (H1N1)-like virus 89(H3N2)-like virus 88-like virus 1992 A/Singapore/6/1986 A/Beijing/353/ B/Yamagata/16/ N/A (H1N1)-like virus 89(H3N2)-like virus 88-like virus 1993 A/Singapore/6/1986 A/Beijing/353/ B/Yamagata/16/ N/A (H1N1)-like virus 89(H3N2)-like virus 88-like virus 1994 A/Singapore/6/1986 A/Beijing/32/ B/Panama/45/ N/A (H1N1)-like virus 92(H3N2)-like virus 90-like virus 1995 A/Singapore/6/1986 A/Shangdong/9/ B/Panama/45/ N/A (H1N1)-like virus 93(H3N2)-like virus 90-like virus 1996 A/Singapore/6/1986 A/Johannesburg/33/ B/Beijing/184/ N/A (H1N1)-like virus 94(H3N2)-like virus 93-like virus 1997 A/Singapore/6/1986 A/Wuhan/359/ B/Beijing/184/ N/A (H1N1)-like virus 95(H3N2)-like virus 93-like strain 1998 A/Bayern/7/ A/Wuhan/359/ B/Beijing/184/ N/A 95(H1N1)-like virus 95(H3N2)-like virus 93-like virus 1999 A/Beijing/262/ A/Sydney/5/ B/Beijing/184/ N/A 95(H1N1)-like virus 97(H3N2)-like virus 93-like virus

TABLE 4 Influenza Vaccine components by year-Northern Hemisphere additional Northern B-strain hemisphere H1N1 H3N2 B-strain for QIV November 1998- A/Beijing/262/ A/Sydney/5/ B/Beijing/184/ N/A April 1999 95(H1N1)-like virus 97(H3N2)-like virus 93-like virus November 1999- A/Beijing/262/95 A/Sydney/5/97 B/Beijing/184/ N/A April 2000 (H1N1)-like virus (H3N2)-like virus 93-like virus or B/Shangdong/7/ 97-like virus 2000-2001 A/New Caledonia/20/ A/Moscow/10/99 B/Beijing/184/ N/A 99(H1N1)-like virus (H3N2)-like virus 93-like virus 2001-2002 A/New Caledonia/20/ A/Moscow/10/ B/Sichuan/379/ N/A 99(H1N1)-like virus 99(H3N2)-like virus 99-like virus 2002-2003 A/New Caledonia/20/ A/Moscow/10/ B/Hong Kong/330/ N/A 99(H1N1)-like virus 99(H3N2)-like virus 2001-like virus 2003-2004 A/New Caledonia/20/ A/Moscow/10/ B/Hong Kong/330/ N/A 99(H1N1)-like virus 99(H3N2)-like virus 2001-like virus 2004-2005 A/New Caledonia/20/ A/Fujian/411/ B/Shanghai/361/ N/A 99(H1N1)-like virus 2002(H3N2)-like virus 2002-like virus 2005-2006 A/New Caledonia/20/ A/California/7/2004 B/Shanghai/361/ N/A 99(H1N1)-like virus (H3N2)-like virus 2002-like virus 2006-2007 A/New Caledonia/20/ A/Wisconsin/67/2005 B/Malaysia/2506/ N/A 99(H1N1)-like (H3N2)-like virus 2004-like virus 2007-2008 A/Solomon Islands/3/2006 A/Wisconsin/67/2005 B/Malaysia/2506/ N/A (H1N1)-like virus (H3N2)-like virus 2004-like virus 2008-2009 A/Brisbane/59/2007 A/Brisbane/10/2007 B/Florida/4/ N/A (H1N1)-like virus (H3N2)-like virus 2006-like virus 2009-2010 A/Brisbane/59/2007 A/Brisbane/10/2007 B/Brisbane/60/ N/A (H1N1)-like virus (H3N2)-like virus 2008-like virus 2010-2011 A/California/7/2009 A/Perth/16/2009 B/Brisbane/60/ N/A (H1N1)-like virus (H3N2)-like virus 2008-like virus 2011-2012 A/California/7/2009 A/Perth/16/2009 B/Brisbane/60/ N/A (H1N1)-like virus (H3N2)-like virus 2008-like virus 2012-2013 A/California/7/2009 A/Victoria/361/2011 B/Wisconsin/1/ B/Brisbane/60/ (H1N1)pdm09-like virus (H3N2)-like virus 2010-like virus 2008-like virus 2013-2014 A/California/7/2009 A(H3N2) virus B/Massachusetts/2/ B/Brisbane/60/ (H1N1)pdm09-like virus antigenically like 2012-like virus 2008-like virus the cell-propagated prototype virus A/Victoria/361/2011 2014-2015 A/California/7/2009 A/Texas/50/2012 B/Massachusetts/2/ B/Brisbane/60/ (H1N1)pdm09-like virus (H3N2)-like virus 2012-like virus 2008-like virus

TABLE 5 Influenza Vaccine components by year-Southern Hemisphere additional Southern B-strain hemisphere H1N1 H3N2 B-strain for QIV 1999 A/Beijing/262/ A/Sydney/5/ B/Beijing/184/ N/A 95(H1N1)-like virus 97(H3N2)-like virus 93-like virus May-October A/New Caledonia/20/99 A/Moscow/10/99 B/Beijing/184/ N/A 2000 (H1N1)-like virus (H3N2)-like virus 93-like virus or B/Shangdong/7/ 97-like virus May-October A/New Caledonia/20/99 A/Moscow/10/99 B/Sichuan/379/ N/A 2001 (H1N1)-like virus (H3N2)-like virus 99-like virus 2002 A/New Caledonia/20/ A/Moscow/10/ B/Sichuan/379/ N/A 99(H1N1)-like virus 99(H3N2)-like virus 99-like virus 2003 A/New Caledonia/20/ A/Moscow/10/ B/Hong Kong/330/ N/A 99(H1N1)-like virus 99(H3N2)-like virus 2001-like virus 2004 A/New Caledonia/20/ A/Fujian/411/ B/Hong Kong/330/ N/A 99(H1N1)-like virus 2002(H3N2)-like virus 2001-like virus 2005 A/New Caledonia/20/ A/Wellington/1/ B/Shanghai/361/ N/A 99(H1N1)-like virus 2004(H3N2)-like virus 2002-like virus 2006 A/New Caledonia/20/ A/California/7/2004 B/Malaysia/2506/ N/A 99(H1N1)-like virus (H3N2)-like virus 2004-like virus 2007 A/New Caledonia/20/ A/Wisconsin/67/ B/Malaysia/2506/ N/A 99(H1N1)-like 2005 (H3N2)-like virus 2004-like virus 2008 A/Solomon Islands/3/2006 A/Brisbane/10/ B/Florida/4/ N/A (H1N1)-like virus 2007(H3N2)-like virus 2006-like virus 2009 A/Brisbane/59/2007 A/Brisbane/10/2007 B/Florida/4/ N/A (H1N1)-like virus (H3N2)-like virus 2006-like virus 2010 A/California/7/2009 A/Perth/16/2009 B/Brisbane/60/ N/A (H1N1)-like virus (H3N2)-like virus 2008-like virus 2011 A/California/7/2009 A/Perth/16/2009 B/Brisbane/60/ N/A (H1N1)-like virus (H3N2)-like virus 2008-like virus 2013 A/California/7/2009 A/Perth/16/2009 B/Brisbane/60/ N/A (H1N1)pdm09 like virus (H3N2)-like virus 2008-like virus 2013 A/California/7/2009 A/Victoria/361/2011 B/Wisconsin/1/ B/Brisbane/60/ (H1N1)pdm09-like virus (H3N2)-like virus 2010-like virus 2008-like virus 2014 A/California/7/2009 A/Texas/50/2012 B/Massachusetts/2/ B/Brisbane/60/ (H1N1)pdm09-like virus (H3N2)-like virus 2012-like virus 2008-like virus

Influenza Antigens

In some embodiments, the NAV polnynucleotides may encode one or more polypeptides of an influenza strain as an antigen. Such antigens include, but are not limited to those antigens encoded by the polynucleotides listed in Tables 6-18. In the table, the GenBank Accession Number represents either the complete or partial CDS of the encoded antigen. The NAV polynucleotides may comprise a region of any of the sequences listed in the tables or entire coding region of the mRNA listed. They may comprise hybrid or chimeric regions, or mimics or variants.

Any of the strains referred to in Tables 6-14 may also be used in an antigenic memory booster vaccine as described herein.

TABLE 6 Influenza H1N1 Antigens GenBank/GI Accession Strain/Protein Length No. Influenza A virus (A/Bayern/7/95(H1N1)) 1,459 AJ518104.1 NA gene for neuraminidase, genomic RNA bp GI:31096418 linear mRNA Influenza A virus (A/Brazil/11/1978(X- 1,072 X86654.1 71)(H1N1)) mRNA for hemagglutinin HA1, bp GI:995549 escape variant 1 linear mRNA Influenza A virus (A/Brazil/11/1978(X- 1,072 X86655.1 71)(H1N1)) mRNA for hemagglutinin HA1, bp GI:995550 escape variant 2 linear mRNA Influenza A virus (A/Brazil/11/1978(X- 1,072 X86656.1 71)(H1N1)) mRNA for hemagglutinin HA1, bp GI:995551 escape variant 3 linear mRNA Influenza A virus (A/Brazil/11/1978(X- 1,072 X86657.1 71)(H1N1)) mRNA for hemagglutinin HA1, bp GI:995552 escape variant 4 linear mRNA Influenza A virus 1,220 AF116575.1 (A/Brevig_Mission/1/18(H1N1)) bp GI:4325017 hemagglutinin (HA) mRNA, partial cds linear mRNA Influenza A virus 1,410 AF250356.2 (A/Brevig_Mission/1/18(H1N1)) bp GI:13260556 neuraminidase (NA) gene, complete cds linear mRNA Influenza A virus (A/Brevig 1,497 AY744935.1 Mission/1/1918(H1N1)) nucleoprotein (np) bp GI:55273940 mRNA, complete cds linear mRNA Influenza A virus (A/Brevig 2,280 DQ208309.1 Mission/1/1918(H1N1)) polymerase PB2 bp GI:76786704 (PB2) mRNA, complete cds linear mRNA Influenza A virus (A/Brevig 2,274 DQ208310.1 Mission/1/1918(H1N1)) polymerase PB1 bp GI:76786706 (PB1) mRNA, complete cds linear mRNA Influenza A virus (A/Brevig 2,151 DQ208311.1 Mission/1/1918(H1N1)) polymerase PA (PA) bp GI:76786708 mRNA, complete cds linear mRNA Influenza A virus 366 bp M73975.1 (A/camel/Mongolia/1982(H1N1)) linear GI:324242 hemagglutinin mRNA, partial cds mRNA Influenza A virus 460 bp M73978.1 (A/camel/Mongolia/1982(H1N1)) matrix linear GI:324402 protein mRNA, partial cds mRNA Influenza A virus 310 bp M73976.1 (A/camel/Mongolia/1982(H1N1)) linear GI:324579 neuraminidase (NA) mRNA, partial cds mRNA Influenza A Virus A/camel/Mongolia/82 NS1 273 bp M73977.1 protein mRNA, partial cds linear GI:324768 mRNA Influenza A virus 227 bp M73974.1 (A/camel/Mongolia/1982(H1N1)) PA linear GI:324931 polymerase mRNA, partial cds mRNA Influenza A virus 531 bp M73973.1 (A/camel/Mongolia/1982(H1N1)) PB1 linear GI:324971 protein mRNA, partial cds mRNA Influenza A Virus (A/camel/Mongolia/82 379 bp M73972.1 (H1N1)) polymerase 2 (P2) mRNA, linear GI:324993 partial cds mRNA Influenza A virus (A/chicken/Hong 1,169 U46782.1 Kong/14/1976(H1N1)) hemagglutinin bp GI:1912328 precursor (HA) mRNA, partial cds linear mRNA Influenza A virus (A/Chonnam/07/2002 1,452 AY297141.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31871990 complete cds linear mRNA Influenza A virus (A/Chonnam/07/2002 1,137 AY297154.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140347 partial cds linear mRNA Influenza A virus (A/Chonnam/18/2002 1,458 AY297143.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31871994 complete cds linear mRNA Influenza A virus (A/Chonnam/18/2002 1,176 AY297156.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140355 partial cds linear mRNA Influenza A virus (A/Chonnam/19/2002 1,458 AY310410.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31872389 complete cds linear mRNA Influenza A virus (A/Chonnam/19/2002 1,167 AY299502.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140392 partial cds linear mRNA Influenza A virus (A/Chonnam/51/2002 1,443 AY310412.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31873090 complete cds linear mRNA Influenza A virus (A/Chonnam/51/2002 1,161 AY299498.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140384 partial cds linear mRNA Influenza A virus (A/Chungbuk/50/2002 1,425 AY297150.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31872010 partial cds linear mRNA Influenza A virus (A/Chungbuk/50/2002 1,161 AY299506.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140400 partial cds linear mRNA Influenza A virus (A/Denmark/40/2000 1,458 AJ518095.1 (H1N1)) NA gene for neuraminidase, bp GI:31096400 genomic RNA linear mRNA Influenza A virus (A/Denver/1/57(H1N1)) 379 bp AF305216.1 neuraminidase mRNA, partial cds linear GI:10732818 mRNA Influenza A virus (A/Denver/1/57(H1N1)) 442 bp AF305217.1 matrix protein gene, partial cds linear GI:10732820 mRNA Influenza A virus (A/Denver/1/57(H1N1)) 215 bp AF305218.1 hemagglutinin gene, partial cds linear GI:10732822 mRNA Influenza A virus (A/duck/ 981 bp U47309.1 Australia/749/80(H1N1)) hemagglutinin linear GI:1912348 precursor (HA) mRNA, partial cds mRNA Influenza A virus 1,777 AF091312.1 (A/duck/Australia/749/80(H1N1)) segment 4 bp GI:4585166 hemagglutinin precursor (HA) mRNA, linear complete cds mRNA Influenza A virus (A/duck/Bavaria/1/77 1,777 AF091313.1 (H1N1)) segment 4 hemagglutinin precursor bp GI:4585168 (HA) mRNA, complete cds linear mRNA Influenza A virus (A/duck/Bavaria/2/77 981 bp U47308.1 (H1N1)) hemagglutinin precursor (HA) linear GI:1912346 mRNA, partial cds mRNA Influenza A virus (A/duck/Eastern 1,458 EU429749.1 China/103/2003(H1N1)) segment 6 bp GI:167859463 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus (A/duck/Eastern 1,461 EU429751.1 China/152/2003(H1N1)) segment 6 bp GI:167859467 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus (A/Duck/Ohio/118C/93 1,410 AF250361.2 (H1N1)) neuraminidase (NA) gene, complete bp GI:13260576 cds linear mRNA Influenza A virus (A/Duck/Ohio/175/86 1,410 AF250358.2 (H1N1)) neuraminidase (NA) gene, bp GI:13260565 complete cds linear mRNA Influenza A virus (A/Duck/Ohio/194/86 1,410 AF250360.2 (H1N1)) neuraminidase (NA) gene, bp GI:13260573 complete cds linear mRNA Influenza A virus (A/Duck/Ohio/30/86 1,410 AF250359.2 (H1N1)) neuraminidase (NA) gene, bp GI:13260570 complete cds linear mRNA Influenza A virus strain 1,460 AJ006954.1 A/Fiji/15899/83(H1N1) mRNA for bp GI:4210707 neuraminidase linear mRNA Influenza A Virus (A/Fiji/15899/83(H1N1)) 2,341 AJ564805.1 mRNA for PB2 protein bp GI:31442134 linear mRNA Influenza A Virus (A/Fiji/15899/83(H1N1)) 2,113 AJ564807.1 partial mRNA for PB1 protein bp GI:31442138 linear mRNA Influenza A virus (A/FM/1/47 (H1N1)) 1,395 AF250357.2 neuraminidase (NA) gene, complete cds bp GI:13260561 linear mRNA Influenza A virus (A/goose/Hong 1,091 U46021.1 Kong/8/1976(H1N1)) hemagglutinin bp GI:1912326 precursor (HA) mRNA, partial cds linear mRNA Influenza A virus (A/goose/Hong 261 bp U48284.1 Kong/8/1976(H1N1)) polymerase (PB1) linear GI:1912372 mRNA, partial cds mRNA Influenza A virus (A/goose/Hong 1,395 U49093.1 Kong/8/1976(H1N1)) nucleoprotein (NP) bp GI:1912384 mRNA, partial cds linear mRNA Influenza A virus 1,775 EU382986.1 (A/Guangzhou/1561/2006(H1N1)) segment 4 bp GI:170762603 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,462 EU382993.1 (A/Guangzhou/1561/2006(H1N1)) segment 6 bp GI:170762617 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,775 EU382987.1 (A/Guangzhou/1684/2006(H1N1)) segment 4 bp GI:170762605 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,462 EU382994.1 (A/Guangzhou/1684/2006(H1N1)) segment 6 bp GI:170762619 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,775 EU382981.1 (A/Guangzhou/483/2006(H1N1)) segment 4 bp GI:170762593 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,462 EU382988.1 (A/Guangzhou/483/2006(H1N1)) segment 6 bp GI:170762607 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,775 EU382982.1 (A/Guangzhou/506/2006(H1N1)) segment 4 bp GI:170762595 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,461 EU382989.1 (A/Guangzhou/506/2006(H1N1)) segment 6 bp GI:170762609 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,775 EU382983.1 (A/Guangzhou/555/2006(H1N1)) segment 4 bp GI:170762597 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,462 EU382990.1 (A/Guangzhou/555/2006(H1N1)) segment 6 bp GI:170762611 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,775 EU382984.1 (A/Guangzhou/657/2006(H1N1)) segment 4 bp GI:170762599 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,462 EU382991.1 (A/Guangzhou/657/2006(H1N1)) segment 6 bp GI:170762613 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,775 EU382985.1 (A/Guangzhou/665/2006(H1N1)) segment 4 bp GI:170762601 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,462 EU382992.1 (A/Guangzhou/665/2006(H1N1)) segment 6 bp GI:170762615 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus (A/Gwangju/55/2002 1,431 AY297151.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31872012 complete cds linear mRNA Influenza A virus (A/Gwangju/55/2002 1,179 AY299507.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140402 partial cds linear mRNA Influenza A virus (A/Gwangju/57/2002 1,446 AY297152.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31872014 complete cds linear mRNA Influenza A virus (A/Gwangju/57/2002 1,167 AY299508.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140404 partial cds linear mRNA Influenza A virus (A/Gwangju/58/2002 1,434 AY297153.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31872016 complete cds linear mRNA Influenza A virus (A/Gwangju/58/2002 1,176 AY299509.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140406 partial cds linear mRNA Influenza A virus (A/Gwangju/90/2002 1,446 AY297147.1 (H1N1)) neuraminidase (NA) mRNA, bp GI:31872002 complete cds linear mRNA Influenza A virus (A/Gwangju/90/2002 1,164 AY299499.1 (H1N1)) hemagglutinin (HA) mRNA, bp GI:32140386 partial cds linear mRNA Influenza A virus (A/Hong 1,403 AJ518101.1 Kong/437/2002(H1N1)) partial NA gene for bp GI:31096412 neuraminidase, genomic RNA linear mRNA Influenza A virus (A/Hong 1,352 AJ518102.1 Kong/747/2001(H1N1)) partial NA gene for bp GI:31096414 neuraminidase, genomic RNA linear mRNA Influenza A virus (A/London/1/1918(H1N1)) 563 bp AY184805.1 hemagglutinin (HA) mRNA, partial cds linear GI:32395285 mRNA Influenza A virus (A/London/1/1919(H1N1)) 563 bp AY184806.1 hemagglutinin (HA) mRNA, partial cds linear GI:32395287 mRNA Influenza A virus (A/Loygang/4/1957 1,565 M76604.1 (H1N1)) nucleoprotein mRNA, complete cds bp GI:324255 linear mRNA Influenza A virus (A/Lyon/651/2001(H1N1)) 1,318 AJ518103.1 partial NA gene for neuraminidase, genomic bp GI:31096416 RNA linear mRNA Influenza A virus (A/mallard/Alberta/119/98 947 bp AY664487.1 (H1N1)) nonfunctional matrix protein mRNA, linear GI:51011891 partial sequence mRNA Influenza A virus 981 bp U47310.1 (A/duck/Alberta/35/76(H1N1)) hemagglutinin linear GI:1912350 precursor (HA) mRNA, partial cds mRNA Influenza A virus 1,777 AF091309.1 (A/duck/Alberta/35/76(H1N1)) segment 4 bp GI:4585160 hemagglutinin precursor (HA) mRNA, linear complete cds mRNA Influenza A virus 1,410 AF250362.2 (A/duck/Alberta/35/76(H1N1)) neuraminidase bp GI:13260579 (NA) gene, complete cds linear mRNA Influenza A virus 981 bp U47307.1 (A/mallard/Tennessee/11464/85 (H1N1)) linear GI:1912344 hemagglutinin precursor (HA) mRNA, partial mRNA cds Influenza A virus 1,777 AF091311.1 (A/mallard/Tennessee/11464/85 (H1N1)) bp GI:4585164 segment 4 hemagglutinin precursor (HA) linear mRNA, complete cds mRNA Influenza A virus (A/New 294 bp HQ008884.1 Caledonia/20/1999(H1N1)) segment 7 matrix linear GI:302566794 protein 2 (M2) mRNA, complete cds mRNA Influenza A virus (A/New Jersey/4/1976 1,565 M76605.1 (H1N1)) nucleoprotein mRNA, complete cds bp GI:324581 linear mRNA Influenza A virus (A/New Jersey/8/1976 1,565 M76606.1 (H1N1)) nucleoprotein mRNA, complete cds bp GI:324583 linear mRNA Influenza A virus (A/New_York/1/18(H1N1)) 1,220 AF116576.1 hemagglutinin (HA) mRNA, partial cds bp GI:4325019 linear mRNA Influenza A virus (A/Ohio/3523/1988(H1N1)) 1,565 M76602.1 nucleoprotein mRNA, complete cds bp GI:324889 linear mRNA Influenza A virus (A/Pusan/22/2002(H1N1)) 1,455 AY310411.1 neuraminidase (NA) mRNA, complete cds bp GI:31872391 linear mRNA Influenza A virus (A/Pusan/22/2002(H1N1)) 1,149 AY299503.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140394 linear mRNA Influenza A virus (A/Pusan/23/2002(H1N1)) 1,440 AY297144.1 neuraminidase (NA) mRNA, complete cds bp GI:31871996 linear mRNA Influenza A virus (A/Pusan/23/2002(H1N1)) 1,158 AY297157.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140357 linear mRNA Influenza A virus (A/Pusan/24/2002(H1N1)) 1,449 AY297145.1 neuraminidase (NA) mRNA, complete cds bp GI:31871998 linear mRNA Influenza A virus (A/Pusan/24/2002(H1N1)) 1,128 AY299494.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140376 linear mRNA Influenza A virus (A/Pusan/44/2002(H1N1)) 1,431 AY297148.1 neuraminidase (NA) mRNA, complete cds bp GI:31872004 linear mRNA Influenza A virus (A/Pusan/44/2002(H1N1)) 1,167 AY299504.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140396 linear mRNA Influenza A virus (A/Pusan/45/2002(H1N1)) 1,434 AY297146.1 neuraminidase (NA) mRNA, complete cds bp GI:31872000 linear mRNA Influenza A virus (A/Pusan/45/2002(H1N1)) 1,167 AY299496.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140380 linear mRNA Influenza A virus (A/Pusan/46/2002(H1N1)) 1,422 AY310408.1 neuraminidase (NA) mRNA, complete cds bp GI:31872385 linear mRNA Influenza A virus (A/Pusan/46/2002(H1N1)) 1,176 AY299497.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140382 linear mRNA Influenza A virus (A/Pusan/47/2002(H1N1)) 1,437 AY297149.1 neuraminidase (NA) mRNA, complete cds bp GI:31872008 linear mRNA Influenza A virus (A/Pusan/47/2002(H1N1)) 1,170 AY299505.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140398 linear mRNA Influenza A virus (A/Saudi 789 bp AJ519463.1 Arabia/7971/2000(H1N1)) partial linear GI:31096450 NS1 gene for non structural mRNA protein 1 and partial N52 gene for non structural protein 2, genomic RNA Influenza A virus (A/Seou1/11/2002(H1N1)) 1,452 AY297142.1 neuraminidase (NA) mRNA, complete cds bp GI:31871992 linear mRNA Influenza A virus (A/Seou1/11/2002(H1N1)) 1,176 AY297155.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140349 linear mRNA Influenza A virus (A/Seou1/13/2002(H1N1)) 1,452 AY310409.1 neuraminidase (NA) mRNA, complete cds bp GI:31872387 linear mRNA Influenza A virus (A/Seou1/13/2002(H1N1)) 1,167 AY299500.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140388 linear mRNA Influenza A virus (A/Seou1/15/2002(H1N1)) 1,449 AY297140.1 neuraminidase (NA) mRNA, complete cds bp GI:31871988 linear mRNA Influenza A virus (A/Seou1/15/2002(H1N1)) 1,149 AY299501.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140390 linear mRNA Influenza A virus (A/Seou1/33/2002(H1N1)) 1,437 AY310407.1 neuraminidase (NA) mRNA, complete cds bp GI:31872383 linear mRNA Influenza A virus (A/Seou1/33/2002(H1N1)) 1,167 AY299495.1 hemagglutinin (HA) mRNA, partial cds bp GI:32140378 linear mRNA Influenza A virus 1,050 Z46437.1 (A/swine/Arnsberg/6554/1979(H1N1)) bp GI:565609 mRNA for hemagglutinin HAI linear mRNA Influenza A virus 1,595 U46783.1 (A/swine/Beijing/47/1991(H1N1)) bp GI:1912330 hemagglutinin precursor (HA) mRNA, linear partial cds mRNA Influenza A virus 1,565 U49091.1 (A/swine/Beijing/94/1991(H1N1)) bp GI:1912380 nucleoprotein (NP) mRNA, complete cds linear mRNA Influenza A virus 1,778 AF091316.1 (A/swine/Belgium/1/83(H1N1)) segment 4 bp GI:4585174 hemagglutinin precursor (HA) mRNA, linear complete cds mRNA Influenza A virus (A/swine/Cotes 1,116 AM490219.1 d'Armor/0118/2006(H1N1)) partial mRNA for bp GI:222062898 haemagglutinin precursor (HAI gene) linear mRNA Influenza A virus (A/swine/Cotes 1,043 AM490223.1 d'Armor/0136_18/2006(H1N1)) partial mRNA bp GI:222062906 for haemagglutinin precursor (HAI gene) linear mRNA Influenza A virus (A/swine/Cotes 1,089 AM490220.1 d'Armor/0184/2006(H1N1)) partial mRNA for bp GI:222062900 haemagglutinin precursor (HAI gene) linear mRNA Influenza A virus (A/swine/Cotes 1,068 AM490221.1 d'Armor/0227/2005(H1N1)) partial mRNA for bp GI:222062902 haemagglutinin precursor (HAI gene) linear mRNA Influenza A virus (A/swine/Cotes 1,024 AM490222.1 d'Armor/0250/2006(H1N1)) partial mRNA for bp GI:222062904 haemagglutinin precursor (HAI gene) linear mRNA Influenza A virus (A/swine/Cotes 1,011 AJ517820.1 d'Armor/736/2001(H1N1)) partial HA gene bp GI:38422533 for Haemagglutinin, genomic RNA linear mRNA Influenza A virus (A/Swine/England/ 1,410 AF250366.2 195852/92 (H1N1)) neuraminidase (NA) bp GI:13260593 gene, complete cds linear mRNA Influenza A virus PB2 gene for Polymerase 2 2,268 AJ311457.1 protein, genomic RNA, strain bp GI:13661037 A/Swine/Finistere/2899/82 linear mRNA Influenza A virus PB1 gene for Polymerase 1 2,341 AJ311462.1 protein, genomic RNA, strain bp GI:13661047 A/Swine/Finistere/2899/82 linear mRNA Influenza A virus PA gene for Polymerase A 2,233 AJ311463.1 protein, genomic RNA, strain bp GI:13661049 A/Swine/Finistere/2899/82 linear mRNA Influenza A virus 1,002 AJ316059.1 (A/swine/Finistere/2899/82(H1N1) M1 gene bp GI:20068128 for matrix protein 1 and M2 gene for matrix linear protein 2, genomic RNA mRNA Influenza A virus 864 bp AJ344037.1 (A/swine/Finistere/2899/82(H1N1)) NS1 gene linear GI:20068185 for non structural protein 1 and NS2 gene for mRNA non structural protein 2, genomic RNA Influenza A virus 838 bp X75786.1 (A/swine/Germany/2/1981(H1N1)) mRNA linear GI:438106 for PA polymerase mRNA Influenza A virus 305 bp Z30277.1 (A/swine/Germany/2/1981(H1N1)) mRNA for linear GI:530399 neuraminidase (partial) mRNA Influenza A virus 1,730 Z30276.1 (A/swine/Germany/2/1981(H1N1)) mRNA for bp GI:563490 hemagglutinin linear mRNA 165. Influenza A virus 1,730 Z46434.1 (A/swine/Germany/8533/1991(H1N1)) mRNA bp GI:565611 for hemagglutinin precursor linear mRNA Influenza A virus 1,690 AY852271.1 (A/swine/Guangdong/711/2001(H1N1)) bp GI:60327789 nonfunctional hemagglutinin (HA) mRNA, linear partial sequence mRNA Influenza A virus 1,809 EU163946.1 (A/swine/Haseluenne/IDT2617/03(H1N1)) bp GI:157679548 hemagglutinin mRNA, complete cds linear mRNA Influenza A virus (A/swine/Hokkaido/2/81 981 bp U47306.1 (H1N1)) hemagglutinin precursor (HA) linear GI:1912342 mRNA, partial cds mRNA Influenza A virus (A/swine/Hokkaido/2/81 1,778 AF091306.1 (H1N1)) segment 4 hemagglutinin precursor bp GI:4585154 (HA) mRNA, complete cds linear mRNA Influenza A virus (A/swine/Hong 1,113 U44482.1 Kong/168/1993(H1N1)) hemagglutinin bp GI:1912318 precursor (HA) mRNA, partial cds linear mRNA Influenza A virus (A/swine/Hong 416 bp U47817.1 Kong/168/1993(H1N1)) neuraminidase (NA) linear GI:1912354 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 286 bp U48286.1 Kong/168/1993(H1N1)) polymerase (PB2) linear GI:1912358 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 379 bp U48283.1 Kong/168/1993(H1N1)) polymerase (PB1) linear GI:1912370 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 308 bp U48850.1 Kong/168/1993(H1N1)) polymerase (PA) linear GI:1912376 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 1,397 U49096.1 Kong/168/1993(H1N1)) nucleoprotein (NP) bp GI:1912390 mRNA, partial cds linear mRNA Influenza A virus (A/swine/Hong 1,315 U46020.1 Kong/172/1993(H1N1)) hemagglutinin bp GI:1912324 precursor (HA) mRNA, partial cds linear mRNA Influenza A virus (A/swine/Hong 1,113 U45451.1 Kong/176/1993(H1N1)) hemagglutinin bp GI:1912320 precursor (HA) mRNA, partial cds linear mRNA Influenza A virus (A/swine/Hong 1,330 U45452.1 Kong/273/1994(H1N1)) hemagglutinin bp GI:1912322 precursor (HA) mRNA, partial cds linear mRNA Influenza A virus (A/swine/Hong 241 bp U47818.1 Kong/273/1994(H1N1)) neuraminidase (NA) linear GI:1912356 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 328 bp U48287.1 Kong/273/1994(H1N1)) polymerase (PB2) linear GI:1912360 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 240 bp U48282.1 Kong/273/1994(H1N1)) polymerase (PB1) linear GI:1912368 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 336 bp U48851.1 Kong/273/1994(H1N1)) polymerase (PA) linear GI:1912378 mRNA, partial cds mRNA Influenza A virus (A/swine/Hong 1,422 U49092.1 Kong/273/1994(H1N1)) nucleoprotein (NP) bp GI:1912382 mRNA, partial cds linear mRNA Influenza A virus 1,761 EU163947.1 (A/swine/IDT/Re230/92hp(H1N1)) bp GI:157679550 hemagglutinin mRNA, complete cds linear mRNA Influenza A virus 1,550 L46849.1 (A/swine/IN/1726/1988(H1N1)) nucleoprotein bp GI:954755 (segment 5) mRNA, complete cds linear mRNA Influenza A virus (A/swine/Iowa/15/30 981 bp U47305.1 (H1N1)) hemagglutinin precursor (HA) linear GI:1912340 mRNA, partial cds mRNA Influenza A virus (A/swine/Iowa/15/30 1,778 AF091308.1 (H1N1)) segment 4 hemagglutinin bp GI:4585158 precursor (HA) mRNA, complete cds linear mRNA Influenza A virus (A/Swine/Iowa/30 (H1N1)) 1,410 AF250364.2 neuraminidase (NA) gene, complete cds bp GI:13260586 linear mRNA Influenza A virus (A/swine/Iowa/17672/88 981 bp U47304.1 (H1N1)) hemagglutinin precursor (HA) linear GI:1912338 mRNA, partial cds mRNA Influenza A virus 864 bp AJ519462.1 (A/swine/Italy/3364/00(H1N1)) partial NS1 linear GI:31096447 gene for non structural protein 1 and partial mRNA NS2 gene for non structural protein 2, genomic RNA Influenza A virus (A/swine/Italy- 1,777 AF091315.1 Virus/671/87(H1N1)) segment 4 bp GI:4585172 hemagglutinin precursor (HA) linear mRNA, complete cds mRNA Influenza A Virus 1,028 Z46436.1 (A/swine/Italy/v.147/1981(H1N1)) mRNA for bp GI:854214 hemagglutinin HAI linear mRNA Influenza A virus 1,118 AM490218.1 (A/swine/Morbihan/0070/2005(H1N1)) partial bp GI:222062896 mRNA for haemagglutinin precursor linear (HAI gene) mRNA Influenza A virus 1,770 L09063.1 (A/swine/Nebraska/1/92(H1N1)) HA protein bp GI:290722 mRNA, complete cds linear mRNA Influenza A virus 1,550 L11164.1 (A/swine/Nebraska/1/1992(H1N1)) segment 5 bp GI:290724 nucleoprotein (NP) mRNA, complete cds linear mRNA Influenza A virus 981 bp U46943.1 (A/swine/Netherlands/12/1985(H1N1)) linear GI:1912336 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus 1,776 AF091317.1 (A/swine/Netherlands/12/85(H1N1)) bp GI:4585176 segment 4 hemagglutinin precursor linear (HA) mRNA, complete cds mRNA Influenza A virus 539 bp X75791.1 (A/swine/Netherlands/25/1980(H1N1)) mRNA linear GI:438105 for nucleoprotein mRNA Influenza A virus 981 bp U46942.1 (A/swine/Netherlands/3/1980(H1N1)) linear GI:1912334 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus 1,778 AF091314.1 (A/swine/Netherlands/3/80(H1N1)) segment 4 bp GI:4585170 hemagglutinin precursor (HA) mRNA, linear complete cds mRNA Influenza A virus (A/NJ/11/76 (H1N1)) 1,410 AF250363.2 neuraminidase (NA) gene, complete cds bp GI:13260583 linear mRNA Influenza A virus (A/Swine/Quebec/192/81 1,438 U86144.1 (SwQc81)) neuraminidase mRNA, bp GI:4099318 complete cds linear mRNA Influenza A virus (A/Swine/Quebec/5393/91 1,438 U86145.1 (SwQc91)) neuraminidase mRNA, bp GI:4099320 complete cds linear mRNA Influenza A virus (A/swine/Schleswig- 1,730 Z46435.1 Holstein/1/1992(H1N1)) mRNA for bp GI:854216 hemagglutinin precursor linear mRNA Influenza A Virus (A/swine/Schleswig- 1,554 Z46438.1 Holstein/1/1993(H1N1)) mRNA for bp GI:854222 nucleoprotein linear mRNA Influenza A virus 1,778 AF091307.1 (A/swine/Wisconsin/1/61(H1N1)) segment 4 bp GI:4585156 hemagglutinin precursor (HA) mRNA, linear complete cds mRNA 212. Influenza A virus 1,565 M76607.1 (A/swine/Wisconsin/1/1967(H1N1)) bp GI:325086 nucleoprotein mRNA, complete cds linear mRNA Influenza A virus 1,565 M76608.1 (A/swine/Wisconsin/1915/1988(H1N1)) bp GI:325088 nucleoprotein mRNA, complete cds linear mRNA Influenza A virus 1,550 L46850.1 (A/swine/WI/1915/1988(H1N1)) bp GI:954757 nucleoprotein (segment 5) mRNA, linear complete cds mRNA Influenza A virus 729 bp AJ532568.1 (A/Switzerland/8808/2002(H1N1)) partial m1 linear GI:31096461 gene for matrix protein 1 and partial m2 gene mRNA for matrix protein 2, genomic RNA Influenza A virus 561 bp AF362803.1 (A/human/Taiwan/0012/00(H1N1)) linear GI:14571975 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus 561 bp AF362779.1 (A/human/Taiwan/0016/00(H1N1)) linear GI:14571927 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0016/2000 303 bp AY303752.1 (H1N1)) polymerase basic protein 1 linear GI:32330993 partial cds mRNA Influenza A virus 561 bp AF362780.1 (A/human/Taiwan/0030/00(H1N1)) linear GI:14571929 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0030/2000 303 bp AY303704.1 (H1N1)) polymerase basic protein 1 (PB1) linear GI:32330897 mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0032/2002 494 bp AY604804.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727488 mRNA Influenza A virus (A/Taiwan/0061/2002 494 bp AY604795.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727470 mRNA Influenza A virus (A/Taiwan/0069/2002 494 bp AY604803.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727486 mRNA Influenza A virus (A/Taiwan/0078/2002 494 bp AY604805.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727490 mRNA Influenza A virus (A/Taiwan/0094/2002 494 bp AY604797.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727474 mRNA Influenza A virus (A/Taiwan/0116/2002 494 bp AY604796.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727472 mRNA Influenza A virus 564 bp AF362781.1 (A/human/Taiwan/0130/96(H1N1)) linear GI:14571931 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0130/96 (H1N1)) 303 bp AY303707.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330903 partial cds mRNA Influenza A virus 564 bp AF362782.1 (A/human/Taiwan/0132/96(H1N1)) linear GI:14571933 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0132/96 (H1N1)) 303 bp AY303708.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330905 partial cds mRNA Influenza A virus 564 bp AF362783.1 (A/human/Taiwan/0211/96(H1N1)) linear GI:14571935 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0211/96 (H1N1)) 303 bp AY303709.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330907 partial cds mRNA Influenza A virus 564 bp AF362784.1 (A/human/Taiwan/0235/96(H1N1)) linear GI:14571937 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0235/96 (H1N1)) 303 bp AY303710.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330909 partial cds mRNA Influenza A virus 564 bp AF362785.1 (A/human/Taiwan/0255/96(H1N1)) linear GI:14571939 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0255/96 (H1N1)) 303 bp AY303711.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330911 partial cds mRNA Influenza A virus 564 bp AF362786.1 (A/human/Taiwan/0337/96(H1N1)) linear GI:14571941 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus 564 bp AF362787.1 (A/human/Taiwan/0342/96(H1N1)) linear GI:14571943 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0342/96 (H1N1)) 303 bp AY303714.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330917 partial cds mRNA Influenza A virus 561 bp AF362788.1 (A/human/Taiwan/0464/99(H1N1)) linear GI:14571945 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus 564 bp AF362789.1 (A/human/Taiwan/0562/95(H1N1)) linear GI:14571947 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0562/95 (H1N1)) 303 bp AY303720.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330929 partial cds mRNA Influenza A virus 564 bp AF362790.1 (A/human/Taiwan/0563/95(H1N1)) linear GI:14571949 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0563/95 (H1N1)) 303 bp AY303721.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330931 partial cds mRNA Influenza A virus 564 bp AF362791.1 (A/human/Taiwan/0657/95(H1N1)) linear GI:14571951 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0657/95 (H1N1)) 303 bp AY303724.1 polymerase basic protein 1 (PB1) mRNA, linear GI:32330937 partial cds mRNA Influenza A virus (A/Taiwan/0859/2002 494 bp AY604801.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727482 mRNA Influenza A virus 561 bp AF362792.1 (A/human/Taiwan/0892/99(H1N1)) linear GI:14571953 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/0983/2002 494 bp AY604800.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727480 mRNA Influenza A virus (A/Taiwan/1007/2006 507 bp EU068163.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452199 partial cds mRNA Influenza A virus (A/Taiwan/1015/2006 507 bp EU068171.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452215 partial cds mRNA Influenza A virus (A/Taiwan/112/1996-1 1,176 AF026153.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554950 partial cds linear mRNA Influenza A virus (A/Taiwan/112/1996-2 1,176 AF026154.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554952 partial cds linear mRNA Influenza A virus (A/Taiwan/117/1996-1 1,176 AF026155.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554954 partial cds linear mRNA Influenza A virus (A/Taiwan/117/1996-2 1,176 AF026156.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554956 partial cds linear mRNA Influenza A virus (A/Taiwan/117/1996-3 1,176 AF026157.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554958 partial cds linear mRNA Influenza A virus (A/Taiwan/118/1996-1 1,176 AF026158.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554960 partial cds linear mRNA Influenza A virus (A/Taiwan/118/1996-2 1,176 AF026159.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554962 partial cds linear mRNA Influenza A virus (A/Taiwan/118/1996-3 1,176 AF026160.1 (H1N1)) haemagglutinin (HA) mRNA, bp GI:2554964 partial cds linear mRNA Influenza A virus 561 bp AF362793.1 (A/human/Taiwan/1184/99(H1N1)) linear GI:14571955 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/1184/99 303 bp AY303726.1 (H1N1)) polymerase basic protein 1 linear GI:32330941 (PB1) mRNA, partial cds mRNA Influenza A virus 564 bp AF362794.1 (A/human/Taiwan/1190/95(H1N1)) linear GI:14571957 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/1190/95 303 bp AY303727.1 (H1N1)) polymerase basic protein 1 (PB1) linear GI:32330943 mRNA, partial cds mRNA Influenza A virus (A/Taiwan/1523/2003 494 bp AY604808.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727496 mRNA Influenza A virus (A/Taiwan/1566/2003 494 bp AY604806.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727492 mRNA Influenza A virus (A/Taiwan/1769/96 875 bp AF138710.2 (H1N1)) matrix protein M1 (M) mRNA, linear GI:4996871 partial cds mRNA Influenza A virus (A/Taiwan/1906/2002 494 bp AY604799.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727478 mRNA Influenza A virus (A/Taiwan/1922/2002 494 bp AY604802.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727484 mRNA Influenza A virus (A/Taiwan/2069/2006 507 bp EU068168.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452209 partial cds mRNA Influenza A virus (A/Taiwan/2157/2001 303 bp AY303733.1 (H1N1)) polymerase basic protein 1 (PB1) linear GI:32330955 mRNA, partial cds mRNA Influenza A virus (A/Taiwan/2175/2001 561 bp AY303734.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:32330957 partial cds mRNA Influenza A virus 564 bp AF362795.1 (A/human/Taiwan/2200/95(H1N1)) linear GI:14571959 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/2200/95 303 bp AY303737.1 (H1N1)) polymerase basic protein 1 (PB1) linear GI:32330963 mRNA, partial cds mRNA Influenza A virus (A/Taiwan/2966/2006 507 bp EU068170.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452213 partial cds mRNA Influenza A virus (A/Taiwan/3168/2005 507 bp EU068174.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452221 partial cds mRNA Influenza A virus 561 bp AF362796.1 (A/human/Taiwan/3355/97(H1N1)) linear GI:14571961 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/3355/97 303 bp AY303739.1 (H1N1)) polymerase basic protein 1 (PB1) linear GI:32330967 mRNA, partial cds mRNA Influenza A virus (A/Taiwan/3361/2001 303 bp AY303740.1 (H1N1)) polymerase basic protein 1 (PB1) linear GI:32330969 mRNA, partial cds mRNA Influenza A virus (A/Taiwan/3361/2001 561 bp AY303741.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:32330971 partial cds mRNA Influenza A virus (A/Taiwan/3518/2006 507 bp EU068169.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452211 partial cds mRNA Influenza A virus 581 bp AF362797.1 (A/human/Taiwan/3825/00(H1N1)) linear GI:14571963 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/3896/2001 303 bp AY303746.1 (H1N1)) polymerase basic protein 1 linear GI:32330981 (PB1) mRNA, partial cds mRNA Influenza A virus (A/Taiwan/3896/2001 561 bp AY303747.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:32330983 partial cds mRNA Influenza A virus (A/Taiwan/4050/2003 494 bp AY604807.1 (H1N1)) hemagglutinin mRNA, partial cds linear GI:50727494 mRNA Influenza A virus (A/Taiwan/615/2006 507 bp EU068162.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452197 partial cds mRNA Influenza A virus (A/Taiwan/645/2006 507 bp EU068164.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452201 partial cds mRNA Influenza A virus (A/Taiwan/680/2005 507 bp EU068173.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452219 partial cds mRNA Influenza A virus (A/Taiwan/719/2006 507 bp EU068158.1 (H1N1)) hemagglutinin (HA) mRNA, linear GI:158452189 partial cds mRNA Influenza A virus 1,410 EU021285.1 (A/Thailand/CU124/2006(H3N2)) bp GI:154224724 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021265.1 (A/Thailand/CU32/2006(H1N1)) bp GI:154224704 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021264.1 (A/Thailand/CU32/2006(H1N1)) bp GI:154224775 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021247.1 (A/Thailand/CU41/2006(H1N1)) bp GI:154224686 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021246.1 (A/Thailand/CU41/2006(H1N1)) bp GI:154224757 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021259.1 (A/Thailand/CU44/2006(H1N1)) bp GI:154224698 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021258.1 (A/Thailand/CU44/2006(H1N1)) bp GI:154224769 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021255.1 (A/Thailand/CU51/2006(H1N1)) bp GI:154224694 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021254.1 (A/Thailand/CU51/2006(H1N1)) bp GI:154224765 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021249.1 (A/Thailand/CU53/2006(H1N1)) bp GI:154224688 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021248.1 (A/Thailand/CU53/2006(H1N1)) bp GI:154224759 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021257.1 (A/Thailand/CU57/2006(H1N1)) bp GI:154224696 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021256.1 (A/Thailand/CU57/2006(H1N1)) bp GI:154224767 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021251.1 (A/Thailand/CU67/2006(H1N1)) bp GI:154224690 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021250.1 (A/Thailand/CU67/2006(H1N1)) bp GI:154224761 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021261.1 (A/Thailand/CU68/2006(H1N1)) bp GI:154224700 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021260.1 (A/Thailand/CU68/2006(H1N1)) bp GI:154224771 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021263.1 (A/Thailand/CU75/2006(H1N1)) bp GI:154224702 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021262.1 (A/Thailand/CU75/2006(H1N1)) bp GI:154224773 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,413 EU021253.1 (A/Thailand/CU88/2006(H1N1)) bp GI:154224692 neuraminidase (NA) mRNA, complete cds linear mRNA Influenza A virus 1,698 EU021252.1 (A/Thailand/CU88/2006(H1N1)) bp GI:154224763 hemagglutinin (HA) mRNA, complete cds linear mRNA Influenza A virus 1,565 M76603.1 (A/turkey/England/647/1977(H1N1)) bp GI:325094 nucleoprotein mRNA, complete cds linear mRNA Influenza A virus 1,445 AJ416626.1 (A/turkey/France/87075/87(H1N1)) Ni gene bp GI:39840719 for neuraminidase, genomic RNA linear mRNA Influenza A virus 394 bp Z30272.1 (A/turkey/Germany/3/91(H1N1)) mRNA linear GI:456652 for PB2 polymerase (partial) mRNA Influenza A virus 97 bp Z30275.1 (A/turkey/Germany/3/91(H1N1)) mRNA for linear GI:530398 neuraminidase (UTR) mRNA Influenza A virus 264 bp Z30274.1 (A/turkey/Germany/3/91(H1N1)) mRNA linear GI:530401 for PA polymerase mRNA Influenza A virus 247 bp Z30273.1 (A/turkey/Germany/3/91(H1N1)) mRNA linear GI:530403 for PBI polymerase (partial) mRNA Influenza A virus 1,038 Z46441.1 (A/turkey/Germany/3/91(H1N1)) mRNA for bp GI:854218 hemagglutinin HAI linear mRNA Influenza A virus 981 bp U46941.1 (A/turkey/Minnesota/1661/1981(H1N1)) linear GI:1912332 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus 1,777 AF091310.1 (A/turkey/Minnesota/1661/81(H1N1)) bp GI:4585162 segment 4 hemagglutinin precursor (HA) linear mRNA, complete cds mRNA Influenza A virus (A/turkey/North 1,565 M76609.1 Carolina/1790/1988(H1N1)) nucleoprotein bp GI:325096 mRNA, complete cds linear mRNA Influenza A virus (A/Weiss/43 (H1N1)) 1,410 AF250365.2 neuraminidase (NA) gene, complete cds bp GI:13260589 linear mRNA Influenza A virus (A/Wilson-Smith/1933 1,497 EU330203.1 (H1N1)) nucleocapsid protein (NP) mRNA, bp GI:167989512 complete cds linear mRNA Influenza A virus 241 bp U47816.1 (A/Wisconsin/3523/1988(H1N1)) linear GI:1912352 neuraminidase (NA) mRNA, partial cds mRNA Influenza A virus 1,565 M76610.1 (A/Wisconsin/3623/1988(H1N1)) bp GI:325103 nucleoprotein mRNA, complete cds linear mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 235 bp U53156.1 PB1 (PB1) mRNA, partial cds linear GI:1399590 mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 168 bp U53158.1 PB2 (PB2) mRNA, partial cds linear GI:1399594 mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 621 bp U53160.1 PA (PA) mRNA, partial cds linear GI:1399598 mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 1,778 U53162.1 hemagglutinin (HA) mRNA, complete cds bp GI:1399602 linear mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 200 bp U53164.1 NP (NP) mRNA, partial cds linear GI:1399606 mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 1,458 U53166.1 neuraminidase (NA) mRNA, complete cds bp GI:1399610 linear mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 1,027 U53168.1 M (M) mRNA, complete cds bp GI:1399614 linear mRNA Influenza A virus (A/WI/4754/1994(H1N1)) 890 bp U53170.1 NS (NS) mRNA, complete cds linear GI:1399618 mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 203 bp U53157.1 PB1 (PB1) mRNA, partial cds linear GI:1399592 mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 173 bp U53159.1 PB2 (PB2) mRNA, partial cds linear GI:1399596 mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 621 bp U53161.1 PA (PA) mRNA, partial cds linear GI:1399600 mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 1,778 U53163.1 hemagglutinin (HA) mRNA, complete cds bp GI:1399604 linear mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 215 bp U53165.1 NP (NP) mRNA, partial cds linear GI:1399608 mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 209 bp U53167.1 neuraminidase (NA) mRNA, partial cds linear GI:1399612 mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 1,027 U53169.1 M (M) mRNA, complete cds bp GI:1399616 linear mRNA Influenza A virus (A/WI/4755/1994(H1N1)) 890 bp U53171.1 NS (NS) mRNA, complete cds linear GI:1399620 mRNA Influenza A virus (A/WSN/33) segment 5 543 bp AF306656.1 nucleocapsid protein (NP) mRNA, partial cds linear GI:11935089 mRNA

TABLE 7 Influenza H3N2 Antigens GenBank/GI Strain/Protein Length Accession No. 1. Influenza A virus 1,704 bp EF614248.1 (A/Aichi/2/1968(H3N2)) hemagglutinin linear GI:148910819 (HA) mRNA, complete cds mRNA 2. Influenza A virus 1,698 bp EF614249.1 (A/Aichi/2/1968(H3N2)) hemagglutinin linear GI:148910821 (HA) mRNA, partial cds mRNA 3. Influenza A virus 1,698 bp EF614250.1 (A/Aichi/2/1968(H3N2)) hemagglutinin linear GI:148910823 (HA) mRNA, partial cds mRNA 4. Influenza A virus 1,698 bp EF614251.1 (A/Aichi/2/1968(H3N2)) hemagglutinin linear GI:148910825 (HA) mRNA, partial cds mRNA 5. Influenza A virus 1,032 bp U48444.1 (A/Akita/1/1995(H3N2)) linear GI:1574989 haemagglutinin mRNA, partial cds mRNA 6. Influenza A virus 1,041 bp Z46392.1 (A/Beijing/32/1992(H3N2)) mRNA for linear GI:609020 haemagglutinin mRNA 7. Influenza A virus 987 bp AF501516.1 (A/Canada/33312/99(H3N2)) linear GI:21314288 hemagglutinin (HA) mRNA, partial cds mRNA 8. Influenza A virus 987 bp AF297094.1 (A/Charlottesville/10/99 (H3N2)) linear GI:11228917 hemagglutinin mRNA, partial cds mRNA 9. Influenza A virus 987 bp AF297096.1 (A/Charlottesville/49/99 (H3N2)) linear GI:11228921 hemagglutinin mRNA, partial cds mRNA 10. Influenza A virus 987 bp AF297097.1 (A/Charlottesville/69/99 (H3N2)) linear GI:11228923 hemagglutinin mRNA, partial cds mRNA 11. Influenza A virus 987 bp AF297095.1 (A/Charlottesville/73/99 (H3N2)) linear GI:11228919 hemagglutinin mRNA, partial cds mRNA 12. Influenza A virus 1,041 bp Z46393.1 (A/England/1/1993(H3N2)) mRNA for linear GI:609024 haemagglutinin mRNA 13. Influenza A virus 1,041 bp Z46394.1 (A/England/247/1993(H3N2)) mRNA for linear GI:609025 haemagglutinin mRNA 14. Influenza A virus 1,041 bp Z46395.1 (A/England/269/93(H3N2)) mRNA for linear GI:609027 haemagglutinin mRNA 15. Influenza A virus 1,041 bp Z46396.1 (A/England/284/1993(H3N2)) mRNA for linear GI:609029 haemagglutinin mRNA 16. Influenza A virus 1,041 bp Z46397.1 (A/England/286/1993(H3N2)) mRNA for linear GI:609031 haemagglutinin mRNA 17. Influenza A virus 1,041 bp Z46398.1 (A/England/289/1993(H3N2)) mRNA for linear GI:609033 haemagglutinin mRNA 18. Influenza A virus 1,041 bp Z46399.1 (A/England/328/1993(H3N2)) mRNA for linear GI:609035 haemagglutinin mRNA 19. Influenza A virus 1,041 bp Z46400.1 (A/England/346/1993(H3N2)) mRNA for linear GI:609037 haemagglutinin mRNA 20. Influenza A virus 1,041 bp Z46401.1 (A/England/347/1993(H3N2)) mRNA for linear GI:609039 haemagglutinin mRNA 21. Influenza A virus 1,091 bp AF201875.1 (A/England/42/72(H3N2)) linear GI:6470274 hemagglutinin mRNA, partial cds mRNA 22. Influenza A virus 1,041 bp Z46402.1 (A/England/471/1993(H3N2)) mRNA for linear GI:609041 haemagglutinin mRNA 23. Influenza A virus 1,041 bp Z46403.1 (A/England/67/1994(H3N2)) mRNA for linear GI:609043 haemagglutinin mRNA 24. Influenza A virus 1,041 bp Z46404.1 (A/England/68/1994(H3N2)) mRNA for linear GI:609045 haemagglutinin mRNA 25. Influenza A virus 1,041 bp Z46405.1 (A/England/7/1994(H3N2)) mRNA for linear GI:609047 haemagglutinin mRNA 28. Influenza A virus 1,041 bp Z46406.1 (A/Guangdong/25/1993(H3N2)) mRNA for linear GI:609049 haemagglutinin mRNA 29. Influenza A virus (A/Hong 1,091 bp AF201874.1 Kong/1/68(H3N2)) hemagglutinin mRNA, linear GI:6470272 partial cds mRNA 30. Influenza A virus (A/Hong 1,041 bp Z46407.1 Kong/1/1994(H3N2)) mRNA for linear GI:609051 haemagglutinin mRNA 31. Influenza A virus (A/Hong 1,762 bp AF382319.1 Kong/1143/99(H3N2)) hemagglutinin linear GI:14487957 mRNA, complete cds mRNA 32. Influenza A virus (A/Hong 1,762 bp AF382320.1 Kong/1143/99(H3N2)) hemagglutinin linear GI:14487959 mRNA, complete cds mRNA 33. Influenza A virus (A/Hong 1,466 bp AF382329.1 Kong/1143/99(H3N2)) neuraminidase linear GI:14487977 mRNA, complete cds mRNA 34. Influenza A virus (A/Hong 1,466 bp AF382330.1 Kong/1143/99(H3N2)) neuraminidase linear GI:14487979 mRNA, complete cds mRNA 35. Influenza A virus (A/Hong 1,762 bp AY035589.1 Kong/1144/99(H3N2)) hemagglutinin linear GI:14486403 mRNA, complete cds mRNA 36. Influenza A virus (A/Hong 1,762 bp AF382321.1 Kong/1144/99(H3N2)) hemagglutinin linear GI:14487961 mRNA, complete cds mRNA 37. Influenza A virus (A/Hong 1,762 bp AF382322.1 Kong/1144/99(H3N2)) hemagglutinin linear GI:14487963 mRNA, complete cds mRNA 38. Influenza A virus (A/Hong 1,466 bp AF382331.1 Kong/1144/99(H3N2)) neuraminidase linear GI:14487981 mRNA, complete cds mRNA 39. Influenza A virus (A/Hong 1,466 bp AF382332.1 Kong/1144/99(H3N2)) neuraminidase linear GI:14487983 mRNA, complete cds mRNA 40. Influenza A virus (A/Hong 1,762 bp AY035590.1 Kong/1179/99(H3N2)) hemagglutinin linear GI:14486405 mRNA, complete cds mRNA 41. Influenza A virus (A/Hong 1,762 bp AF382323.1 Kong/1179/99(H3N2)) hemagglutinin linear GI:14487965 mRNA, complete cds mRNA 42. Influenza A virus (A/Hong 1,762 bp AF382324.1 Kong/1179/99(H3N2)) hemagglutinin linear GI:14487967 mRNA, complete cds mRNA 43. Influenza A virus (A/Hong 1,762 bp AY035591.1 Kong/1180/99(H3N2)) hemagglutinin linear GI:14486407 mRNA, complete cds mRNA 44. Influenza A virus (A/Hong 1,762 bp AF382325.1 Kong/1180/99(H3N2)) hemagglutinin linear GI:14487969 mRNA, complete cds mRNA 45. Influenza A virus (A/Hong 1,762 bp AF382326.1 Kong/1180/99(H3N2)) hemagglutinin linear GI:14487971 mRNA, complete cds mRNA 46. Influenza A virus (A/Hong 1,762 bp AF382327.1 Kong/1182/99(H3N2)) hemagglutinin linear GI:14487973 mRNA, complete cds mRNA 47. Influenza A virus (A/Hong 1,762 bp AF382328.1 Kong/1182/99(H3N2)) hemagglutinin linear GI:14487975 mRNA, complete cds mRNA 48. Influenza A virus (A/Hong 1,041 bp Z46408.1 Kong/2/1994(H3N2)) mRNA for linear GI:609055 haemagglutinin mRNA 49. Influenza A virus (A/Hong 1,041 bp Z46410.1 Kong/23/1992(H3N2)) mRNA for linear GI:609053 haemagglutinin mRNA 50. Influenza A virus (A/Hong 1,041 bp Z46409.1 Kong/34/1990(H3N2)) mRNA for linear GI:609057 haemagglutinin mRNA 51. Influenza A virus 1,041 bp Z46397.1 (A/England/286/1993(H3N2)) mRNA for linear GI:609031 haemagglutinin mRNA 52. Influenza A virus 1,041 bp Z46398.1 (A/England/289/1993(H3N2)) mRNA for linear GI:609033 haemagglutinin mRNA 53. Influenza A virus 1,041 bp Z46399.1 (A/England/328/1993(H3N2)) mRNA for linear GI:609035 haemagglutinin mRNA 54. Influenza A virus 1,041 bp Z46400.1 (A/England/346/1993(H3N2)) mRNA for linear GI:609037 haemagglutinin mRNA 55. Influenza A virus 1,041 bp Z46401.1 (A/England/347/1993(H3N2)) mRNA for linear GI:609039 haemagglutinin mRNA 56. Influenza A virus 1,091 bp AF201875.1 (A/England/42/72(H3N2)) linear GI:6470274 hemagglutinin mRNA, partial cds mRNA 57. Influenza A virus 1,041 bp Z46402.1 (A/England/471/1993(H3N2)) mRNA for linear GI:609041 haemagglutinin mRNA 58. Influenza A virus 1,041 bp Z46403.1 (A/England/67/1994(H3N2)) mRNA for linear GI:609043 haemagglutinin mRNA 59. Influenza A virus 1,041 bp Z46404.1 (A/England/68/1994(H3N2)) mRNA for linear GI:609045 haemagglutinin mRNA 60. Influenza A virus 1,041 bp Z46405.1 (A/England/7/1994(H3N2)) mRNA for linear GI:609047 haemagglutinin mRNA 63. Influenza A virus 1,032 bp U48442.1 (A/Guandong/28/1994(H3N2)) linear GI:1574985 haemagglutinin mRNA, partial cds mRNA 64. Influenza A virus 1,041 bp Z46406.1 (A/Guangdong/25/1993(H3N2)) mRNA for linear GI:609049 haemagglutinin mRNA 65. Influenza A virus 1,032 bp U48447.1 (A/Hebei/19/1995(H3N2)) linear GI:1574995 haemagglutinin mRNA, partial cds mRNA 66. Influenza A virus 1,032 bp U48441.1 (A/Hebei/41/1994(H3N2)) linear GI:1574983 haemagglutinin mRNA, partial cds mRNA 67. Influenza A virus (A/Hong 1,091 bp AF201874.1 Kong/1/68(H3N2)) hemagglutinin mRNA, linear GI:6470272 partial cds mRNA 68. Influenza A virus (A/Hong 1,041 bp Z46407.1 Kong/1/1994(H3N2)) mRNA for linear GI:609051 haemagglutinin mRNA 69. Influenza A virus (A/Hong 1,762 bp AY035588.1 Kong/1143/99(H3N2)) hemagglutinin linear GI:14486401 mRNA, complete cds mRNA 70. Influenza A virus (A/Hong 1,762 bp AF382319.1 Kong/1143/99(H3N2)) hemagglutinin linear GI:14487957 mRNA, complete cds mRNA 71. Influenza A virus (A/Hong 1,762 bp AF382320.1 Kong/1143/99(H3N2)) hemagglutinin linear GI:14487959 mRNA, complete cds mRNA 72. Influenza A virus (A/Hong 1,466 bp AF382329.1 Kong/1143/99(H3N2)) neuraminidase linear GI:14487977 mRNA, complete cds mRNA 73. Influenza A virus (A/Hong 1,466 bp AF382330.1 Kong/1143/99(H3N2)) neuraminidase linear GI:14487979 mRNA, complete cds mRNA 74. Influenza A virus (A/Hong 1,762 bp AY035589.1 Kong/1144/99(H3N2)) hemagglutinin linear GI:14486403 mRNA, complete cds mRNA 75. Influenza A virus (A/Hong 1,762 bp AF382321.1 Kong/1144/99(H3N2)) hemagglutinin linear GI:14487961 mRNA, complete cds mRNA 76. Influenza A virus (A/Hong 1,762 bp AF382322.1 Kong/1144/99(H3N2)) hemagglutinin linear GI:14487963 mRNA, complete cds mRNA 77. Influenza A virus (A/Hong 1,466 bp AF382331.1 Kong/1144/99(H3N2)) neuraminidase linear GI:14487981 mRNA, complete cds mRNA 78. Influenza A virus (A/Hong 1,466 bp AF382332.1 Kong/1144/99(H3N2)) neuraminidase linear GI:14487983 mRNA, complete cds mRNA 79. Influenza A virus (A/Hong 1,762 bp AY035590.1 Kong/1179/99(H3N2)) hemagglutinin linear GI:14486405 mRNA, complete cds mRNA 80. Influenza A virus (A/Hong 1,762 bp AF382323.1 Kong/1179/99(H3N2)) hemagglutinin linear GI:14487965 mRNA, complete cds mRNA 81. Influenza A virus (A/Hong 1,762 bp AF382324.1 Kong/1179/99(H3N2)) hemagglutinin linear GI:14487967 mRNA, complete cds mRNA 82. Influenza A virus (A/Hong 1,762 bp AY035591.1 Kong/1180/99(H3N2)) hemagglutinin linear GI:14486407 mRNA, complete cds mRNA 83. Influenza A virus (A/Hong 1,762 bp AF382325.1 Kong/1180/99(H3N2)) hemagglutinin linear GI:14487969 mRNA, complete cds mRNA 84. Influenza A virus (A/Hong 1,762 bp AF382326.1 Kong/1180/99(H3N2)) hemagglutinin linear GI:14487971 mRNA, complete cds mRNA 85. Influenza A virus (A/Hong 1,762 bp AY035592.1 Kong/1182/99(H3N2)) hemagglutinin linear GI:14486409 mRNA, complete cds mRNA 86. Influenza A virus (A/Hong 1,762 bp AF382327.1 Kong/1182/99(H3N2)) hemagglutinin linear GI:14487973 mRNA, complete cds mRNA 87. Influenza A virus (A/Hong 1,762 bp AF382328.1 Kong/1182/99(H3N2)) hemagglutinin linear GI:14487975 mRNA, complete cds mRNA 88. Influenza A virus (A/Hong 1,041 bp Z46408.1 Kong/2/1994(H3N2)) mRNA for linear GI:609055 haemagglutinin mRNA 89. Influenza A virus (A/Hong 1,041 bp Z46410.1 Kong/23/1992(H3N2)) mRNA for linear GI:609053 haemagglutinin mRNA 90. Influenza A virus (A/Hong 1,041 bp Z46409.1 Kong/34/1990(H3N2)) mRNA for linear GI:609057 haemagglutinin mRNA 91. Influenza A virus 987 bp AF501534.1 (A/Indiana/28170/99(H3N2)) linear GI:21314324 hemagglutinin (HA) mRNA, partial cds mRNA 92. Influenza A virus 529 bp AY961997.1 (A/Kinmen/618/03(H3N2)) linear GI:68138151 hemagglutinin (HA) mRNA, partial cds mRNA 93. Influenza A virus 383 bp AY973325.1 (A/Kinmen/618/03(H3N2)) linear GI:70673206 neuraminidase (NA) mRNA, partial cds mRNA 94. Influenza A virus 882 bp AY986986.1 (A/Kinmen/618/03(H3N2)) linear GI:70728099 nucleoprotein (NP) mRNA, partial cds mRNA 95. Influenza A virus 545 bp AY962017.1 (A/Kinmen/621/03(H3N2)) linear GI:68138191 hemagglutinin (HA) mRNA, partial cds mRNA 96. Influenza A virus 386 bp AY973326.1 (A/Kinmen/621/03(H3N2)) linear GI:70673208 neuraminidase (NA) mRNA, partial cds mRNA 97. Influenza A virus 882 bp AY986987.1 (A/Kinmen/621/03(H3N2)) linear GI:70728101 nucleoprotein (NP) mRNA, partial cds mRNA 98. Influenza A virus 786 bp AY962008.1 (A/Kinmen/639/04(H3N2)) linear GI:68138173 hemagglutinin (HA) mRNA, partial cds mRNA 99. Influenza A virus 381 bp AY973327.1 (A/Kinmen/639/04(H3N2)) linear GI:70673210 neuraminidase (NA) mRNA, partial cds mRNA 100. Influenza A virus 882 bp AY986988.1 (A/Kinmen/639/04(H3N2)) linear GI:70728103 nucleoprotein (NP) mRNA, partial cds mRNA 101. Influenza A virus 596 bp AY962004.1 (A/Kinmen/641/04(H3N2)) linear GI:68138165 hemagglutinin (HA) mRNA, partial cds mRNA 102. Influenza A virus 785 bp AY973328.1 (A/Kinmen/641/04(H3N2)) linear GI:70673212 neuraminidase (NA) mRNA, partial cds mRNA 103. Influenza A virus 576 bp AY962001.1 (A/Kinmen/642/04(H3N2)) linear GI:68138159 hemagglutinin (HA) mRNA, partial cds mRNA 104. Influenza A virus 580 bp AY973329.1 (A/Kinmen/642/04(H3N2)) linear GI:70673214 neuraminidase (NA) mRNA, partial cds mRNA 105. Influenza A virus 882 bp AY986989.1 (A/Kinmen/642/04(H3N2)) linear GI:70728105 nucleoprotein (NP) mRNA, partial cds mRNA 106. Influenza A virus 789 bp AY962009.1 (A/Kinmen/645/04(H3N2)) linear GI:68138175 hemagglutinin (HA) mRNA, partial cds mRNA 107. Influenza A virus 581 bp AY973330.1 (A/Kinmen/645/04(H3N2)) linear GI:70673216 neuraminidase (NA) mRNA, partial cds mRNA 108. Influenza A virus 981 bp AY986990.1 (A/Kinmen/645/04(H3N2)) linear GI:70728107 nucleoprotein (NP) mRNA, partial cds mRNA 109. Influenza A virus 2,341 bp U62543.1 (A/LosAngeles/2/1987(H3N2)) linear GI:1480737 polymerase protein basic 2 (PB2) mRNA mRNA, complete cds 110. Influenza A virus 1,041 bp Z46411.1 (A/Madrid/252/1993(H3N2)) mRNA for linear GI:609067 haemagglutinin mRNA 111. Influenza A virus 987 bp AF501531.1 (A/Michigan/22568/99(H3N2)) linear GI:21314318 hemagglutinin (HA) mRNA, partial cds mRNA 112. Influenza A virus 987 bp AF501518.1 (A/Michigan/22692/99(H3N2)) linear GI:21314292 hemagglutinin (HA) mRNA, partial cds mRNA 113. Influenza A virus 754 bp AJ519454.1 (A/Moscow/10/99(H3N2)) partial NS1 linear GI:31096423 gene for non structural protein 1 mRNA and partial NS2 gene for non structural protein 2, genomic RNA 114. Influenza A virus 987 bp AY138518.1 (A/ningbo/17/2002(H3N2)) linear GI:24895178 hemagglutinin (HA) mRNA, partial cds mRNA 115. Influenza A virus 987 bp AY138517.1 (A/ningbo/25/2002(H3N2)) linear GI:24895169 hemagglutinin (HA) mRNA, partial cds mRNA 116. Influenza A virus 1,765 bp V01103.1 (A/NT/60/68/29C(H3N2)) mRNA for linear GI:60800 haemagglutinin (HA1 and HA2 genes) mRNA 117. Influenza A virus 1,701 bp DQ059385.1 (A/Oklahoma/323/03(H3N2)) linear GI:66933143 hemagglutinin mRNA, complete cds mRNA 118. Influenza A virus 1,410 bp DQ059384.2 (A/Oklahoma/323/03(H3N2)) linear GI:75859981 neuraminidase mRNA, complete cds mRNA 119. Influenza A virus 766 bp AJ519458.1 (A/Panama/2007/99(H3N2)) partial NS1 linear GI:31096435 gene for non structural protein 1 mRNA and partial NS2 gene for non structural protein 2, genomic RNA 120. Influenza A virus 987 bp AF501526.1 (A/Pennsalvanya/20109/99(H3N2)) linear GI:21314308 hemagglutinin (HA) mRNA, partial cds mRNA 121. Influenza A virus 1,091 bp AF233691.1 (A/Philippines/2/82(H3N2)) linear GI:7331124 hemagglutinin mRNA, partial cds mRNA 122. Influenza A virus 767 bp AY962000.1 (A/Pingtung/303/04(H3N2)) linear GI:68138157 hemagglutinin (HA) mRNA, partial cds mRNA 123. Influenza A virus 783 bp AY973331.1 (A/Pingtung/303/04(H3N2)) linear GI:70673218 neuraminidase (NA) mRNA, partial cds mRNA 124. Influenza A virus 928 bp AY986991.1 (A/Pingtung/303/04(H3N2)) linear GI:70728109 nucleoprotein (NP) mRNA, partial cds mRNA 125. Influenza A virus 788 bp AY961999.1 (A/Pingtung/313/04(H3N2)) linear GI:68138155 hemagglutinin (HA) mRNA, partial cds mRNA 126. Influenza A virus 787 bp AY973332.1 (A/Pingtung/313/04(H3N2)) linear GI:70673220 neuraminidase (NA) mRNA, partial cds mRNA 127. Influenza A virus 882 bp AY986992.1 (A/Pingtung/313/04(H3N2)) linear GI:70728111 nucleoprotein (NP) mRNA, partial cds mRNA 128. Influenza A virus (A/ruddy 927 bp AY664458.1 turnstone/Delaware/142/99 (H3N2)) linear GI:51011862 nonfunctional matrix protein mRNA, mRNA partial sequence 129. Influenza A virus 1,041 bp Z46413.1 (A/Scotland/142/1993(H3N2)) mRNA for linear GI:609059 haemagglutinin mRNA 130. Influenza A virus 1,041 bp Z46414.1 (A/Scotland/160/1993(H3N2)) mRNA for linear GI:609061 haemagglutinin mRNA 131. Influenza A virus 1,041 bp Z46416.1 (A/Scotland/173/1993(H3N2)) mRNA for linear GI:609063 haemagglutinin mRNA 132. Influenza A virus 1,041 bp Z46415.1 (A/Scotland/174/1993(H3N2)) mRNA for linear GI:609065 haemagglutinin mRNA 133. Influenza A virus 1,041 bp Z46412.1 (A/Scotland/2/1993(H3N2)) mRNA for linear GI:609069 haemagglutinin mRNA 134. Influenza A virus 1,032 bp U48439.1 (A/Sendai/c182/1994(H3N2)) linear GI:1574979 haemagglutinin mRNA, partial cds mRNA 135. Influenza A virus 1,032 bp U48445.1 (A/Sendai/c373/1995(H3N2)) linear GI:1574991 haemagglutinin mRNA, partial cds mRNA 136. Influenza A virus 1,032 bp U48440.1 (A/Sendai/c384/1994(H3N2)) linear GI:1574981 haemagglutinin mRNA, partial cds mRNA 137. Influenza A virus 1,041 bp Z46417.1 (A/Shangdong/9/1993(H3N2)) mRNA for linear GI:609071 haemagglutinin mRNA 138. Influenza A virus 987 bp L19416.1 (A/Shanghai/11/1987/X99aE high yield linear GI:348117 reassortant(H3N2)) hemagglutinin mRNA (HA) mRNA, partial cds 139. Influenza A virus 2,280 bp AF225514.1 (A/sw/Shizuoka/110/97(H3N2)) linear GI:27462098 polymerase basic 2 (PB2) mRNA, mRNA complete cds 140. Influenza A virus 2,274 bp AF225518.1 (A/sw/Shizuoka/110/97(H3N2)) linear GI:27462106 polymerase basic 1 (PB1) mRNA, mRNA complete cds 141. Influenza A virus 2,151 bp AF225522.1 (A/sw/Shizuoka/110/97(H3N2)) linear GI:27462114 polymerase acidic (PA) mRNA, mRNA complete cds 142. Influenza A virus 1,497 bp AF225534.1 (A/sw/Shizuoka/110/97(H3N2)) linear GI:27462146 nucleoprotein (NP) mRNA, complete mRNA cds 143. Influenza A virus 1,410 bp AF225538.1 (A/sw/Shizuoka/110/97(H3N2)) linear GI:27462154 neuraminidase (NA) mRNA, complete mRNA cds 144. Influenza A virus 984 bp AF225542.1 (A/sw/Shizuoka/110/97(H3N2)) linear GI:27462162 hemagglutinin (HA1) mRNA, partial mRNA cds 145. Influenza A virus 2,280 bp AF225515.1 (A/sw/Shizuoka/115/97(H3N2)) linear GI:27462100 polymerase basic 2 (PB2) mRNA, mRNA complete cds 146. Influenza A virus 2,274 bp AF225519.1 (A/sw/Shizuoka/115/97(H3N2)) linear GI:27462108 polymerase basic 1 (PB1) mRNA, mRNA complete cds 147. Influenza A virus 2,151 bp AF225523.1 (A/sw/Shizuoka/115/97(H3N2)) linear GI:27462116 polymerase acidic (PA) mRNA, mRNA complete cds 148. Influenza A virus 1,497 bp AF225535.1 (A/sw/Shizuoka/115/97(H3N2)) linear GI:27462148 nucleoprotein (NP) mRNA, complete mRNA cds 149. Influenza A virus 1,410 bp AF225539.1 (A/sw/Shizuoka/115/97(H3N2)) linear GI:27462156 neuraminidase (NA) mRNA, complete mRNA cds 150. Influenza A virus 984 bp AF225543.1 (A/sw/Shizuoka/115/97(H3N2)) linear GI:27462164 hemagglutinin (HA1) mRNA, partial mRNA cds 151. Influenza A virus 2,280 bp AF225516.1 (A/sw/Shizuoka/119/97(H3N2)) linear GI:27462102 polymerase basic 2 (PB2) mRNA, mRNA complete cds 152. Influenza A virus 2,274 bp AF225520.1 (A/sw/Shizuoka/119/97(H3N2)) linear GI:27462110 polymerase basic 1 (PB1) mRNA, mRNA complete cds 153. Influenza A virus 2,151 bp AF225524.1 (A/sw/Shizuoka/119/97(H3N2)) linear GI:27462118 polymerase acidic (PA) mRNA, mRNA complete cds 154. Influenza A virus 1,497 bp AF225536.1 (A/sw/Shizuoka/119/97(H3N2)) linear GI:27462150 nucleoprotein (NP) mRNA, complete mRNA cds 155. Influenza A virus 1,410 bp AF225540.1 (A/sw/Shizuoka/119/97(H3N2)) linear GI:27462158 neuraminidase (NA) mRNA, complete mRNA cds 156. Influenza A virus 984 bp AF225544.1 (A/sw/Shizuoka/119/97(H3N2)) linear GI:27462166 hemagglutinin (HA1) mRNA, partial mRNA cds 159. Influenza A virus 1,410 bp EU163948.1 (A/swine/Bakum/IDT1769/2003(H3N2)) linear GI:157679552 neuraminidase mRNA, complete cds mRNA 163. Influenza A virus 1,738 bp AY857957.1 (A/swine/Fujian/668/01(H3N2)) linear GI:58042507 nonfunctional hemagglutinin mRNA, mRNA complete sequence 164. Influenza A virus PB2 gene for 2,280 bp AJ311459.1 Polymerase 2 protein, genomic RNA, linear GI:13661041 strain A/Swine/Italy/1523/98 mRNA 165. Influenza A virus PB1 gene for 2,274 bp AJ311460.1 Polymerase 1 protein, genomic RNA, linear GI:13661043 strain A/Swine/Italy/1523/98 mRNA 166. Influenza A virus 821 bp AJ344024.1 (A/swine/Italy/1523/98(H3N2)) NS1 linear GI:20068146 gene for non structural protein 1 mRNA and NS2 gene for non structural protein 2, genomic RNA 167. Influenza A virus 1,465 bp EU163949.1 (A/swine/Re220/92hp(H3N2)) linear GI:157679554 neuraminidase mRNA, complete cds mRNA 168. Influenza A virus 2,280 bp AF225517.1 (A/sw/Shizuoka/120/97(H3N2)) linear GI:27462104 polymerase basic 2 (PB2) mRNA, mRNA complete cds 169. Influenza A virus 2,274 bp AF225521.1 (A/sw/Shizuoka/120/97(H3N2)) linear GI:27462112 polymerase basic 1 (PB1) mRNA, mRNA complete cds 170. Influenza A virus 2,151 bp AF225525.1 (A/sw/Shizuoka/120/97(H3N2)) linear GI:27462120 polymerase acidic (PA) mRNA, mRNA complete cds 171. Influenza A virus 1,497 bp AF225537.1 (A/sw/Shizuoka/120/97(H3N2)) linear GI:27462152 nucleoprotein (NP) mRNA, complete mRNA cds 172. Influenza A virus 1,410 bp AF225541.1 (A/sw/Shizuoka/120/97(H3N2)) linear GI:27462160 neuraminidase (NA) mRNA, complete mRNA cds 173. Influenza A virus 984 bp AF225545.1 (A/sw/Shizuoka/120/97(H3N2)) linear GI:27462168 hemagglutinin (HA1) mRNA, partial mRNA cds 174. Influenza A virus 1,762 bp AY032978.1 (A/Switzerland/7729/98(H3N2)) linear GI:14161723 hemagglutinin mRNA, complete cds mRNA 175. Influenza A virus 1,762 bp AF382318.1 (A/Switzerland/7729/98(H3N2)) linear GI:14487955 hemagglutinin mRNA, complete cds mRNA 176. Influenza A virus 528 bp AY962011.1 (A/Tainan/704/03(H3N2)) linear GI:68138179 hemagglutinin (HA) mRNA, partial cds mRNA 177. Influenza A virus 384 bp AY973333.1 (A/Tainan/704/03(H3N2)) linear GI:70673222 neuraminidase (NA) mRNA, partial cds mRNA 178. Influenza A virus 882 bp AY986993.1 (A/Tainan/704/03(H3N2)) linear GI:70728113 nucleoprotein (NP) mRNA, partial cds mRNA 179. Influenza A virus 519 bp AY962012.1 (A/Tainan/712/03(H3N2)) linear GI:68138181 hemagglutinin (HA) mRNA, partial cds mRNA 180. Influenza A virus 383 bp AY973334.1 (A/Tainan/712/03(H3N2)) linear GI:70673224 neuraminidase (NA) mRNA, partial cds mRNA 181. Influenza A virus 882 bp AY986994.1 (A/Tainan/712/03(H3N2)) linear GI:70728115 nucleoprotein (NP) mRNA, partial cds mRNA 182. Influenza A virus 784 bp AY962005.1 (A/Tainan/722/03(H3N2)) linear GI:68138167 hemagglutinin (HA) mRNA, partial cds mRNA 183. Influenza A virus 592 bp AY973335.1 (A/Tainan/722/03(H3N2)) linear GI:70673226 neuraminidase (NA) mRNA, partial cds mRNA 184. Influenza A virus 936 bp AY986995.1 (A/Tainan/722/03(H3N2)) linear GI:70728117 nucleoprotein (NP) mRNA, partial cds mRNA 185. Influenza A virus 788 bp AY961998.1 (A/Taipei/407/03(H3N2)) linear GI:68138153 hemagglutinin (HA) mRNA, partial cds mRNA 186. Influenza A virus 787 bp AY973336.1 (A/Taipei/407/03(H3N2)) linear GI:70673228 neuraminidase (NA) mRNA, partial cds mRNA 187. Influenza A virus 882 bp AY986996.1 (A/Taipei/407/03(H3N2)) linear GI:70728119 nucleoprotein (NP) mRNA, partial cds mRNA 188. Influenza A virus 787 bp AY962007.1 (A/Taipei/416/03(H3N2)) linear GI:68138171 hemagglutinin (HA) mRNA, partial cds mRNA 189. Influenza A virus 782 bp AY973337.1 (A/Taipei/416/03(H3N2)) linear GI:70673230 neuraminidase (NA) mRNA, partial cds mRNA 190. Influenza A virus 882 bp AY986997.1 (A/Taipei/416/03(H3N2)) linear GI:70728121 nucleoprotein (NP) mRNA, partial cds mRNA 191. Influenza A virus 297 bp AY303703.1 (A/Taiwan/0020/98 (H3N2)) polymerase linear GI:32330895 basic protein 1 (PB1) mRNA, partial mRNA cds 192. Influenza A virus 791 bp AY604817.1 (A/Taiwan/0040/2003(H3N2)) linear GI:50727514 hemagglutinin mRNA, partial cds mRNA 193. Influenza A virus 297 bp AY303705.1 (A/Taiwan/0045/98 (H3N2)) polymerase linear GI:32330899 basic protein 1 (PB1) mRNA, partial mRNA cds 194. Influenza A virus 844 bp AF362820.1 (A/human/Taiwan/0095/96(H3N2)) linear GI:15055140 hemagglutinin (HA) mRNA, partial cds mRNA 195. Influenza A virus 791 bp AY604828.1 (A/Taiwan/0097/2003(H3N2)) linear GI:50727536 hemagglutinin mRNA, partial cds mRNA 196. Influenza A virus 297 bp AY303706.1 (A/Taiwan/0104/2001 (H3N2)) linear GI:32330901 polymerase basic protein 1 (PB1) mRNA mRNA, partial cds 197. Influenza A virus 844 bp AF362805.1 (A/human/Taiwan/0118/98(H3N2)) linear GI:15055110 hemagglutinin (HA) mRNA, partial cds mRNA 198. Influenza A virus 791 bp AY604823.1 (A/Taiwan/0122/2003(H3N2)) linear GI:50727526 hemagglutinin mRNA, partial cds mRNA 199. Influenza A virus 844 bp AF362806.1 (A/human/Taiwan/0149/00(H3N2)) linear GI:15055112 hemagglutinin (HA) mRNA, partial cds mRNA 200. Influenza A virus 297 bp AY303712.1 (A/Taiwan/0275/2000 (H3N2)) linear GI:32330913 polymerase basic protein 1 (PB1) mRNA mRNA, partial cds 201. Influenza A virus 844 bp AY303713.1 (A/Taiwan/0275/2000 (H3N2)) linear GI:32330915 hemagglutinin (HA) mRNA, partial cds mRNA 202. Influenza A virus 844 bp AF362807.1 (A/human/Taiwan/0293/98(H3N2)) linear GI:15055114 hemagglutinin (HA) mRNA, partial cds mRNA 203. Influenza A virus 297 bp AY303715.1 (A/Taiwan/0346/98 (H3N2)) polymerase linear GI:32330919 basic protein 1 (PB1) mRNA, partial mRNA cds 204. Influenza A virus 297 bp AY303716.1 (A/Taiwan/0379/2000 (H3N2)) linear GI:32330921 polymerase basic protein 1 (PB1) mRNA mRNA, partial cds 205. Influenza A virus 844 bp AY303717.1 (A/Taiwan/0379/2000 (H3N2)) linear GI:32330923 hemagglutinin (HA) mRNA, partial cds mRNA 206. Influenza A virus 791 bp AY625729.1 (A/Taiwan/0388/2001(H3N2)) linear GI:50604415 hemagglutinin (HA) mRNA, partial cds mRNA 207. Influenza A virus 844 bp AF362808.1 (A/human/Taiwan/0389/99(H3N2)) linear GI:15055116 hemagglutinin (HA) mRNA, partial cds mRNA 208. Influenza A virus 844 bp AF362809.1 (A/human/Taiwan/0423/98(H3N2)) linear GI:15055118 hemagglutinin (HA) mRNA, partial cds mRNA 209. Influenza A virus 297 bp AY303718.1 (A/Taiwan/0423/98 (H3N2)) polymerase linear GI:32330925 basic protein 1 (PB1) mRNA, partial mRNA cds 210. Influenza A virus 844 bp AF362810.1 (A/human/Taiwan/0464/98(H3N2)) linear GI:15055120 hemagglutinin (HA) mRNA, partial cds mRNA 211. Influenza A virus 297 bp AY303719.1 (A/Taiwan/0464/98 (H3N2)) polymerase linear GI:32330927 basic protein 1 (PB1) mRNA, partial mRNA cds 212. Influenza A virus 791 bp AY625730.1 (A/Taiwan/0568/2001(H3N2)) linear GI:50604440 hemagglutinin (HA) mRNA, partial cds mRNA 213. Influenza A virus 791 bp AY604822.1 (A/Taiwan/0570/2003(H3N2)) linear GI:50727524 hemagglutinin mRNA, partial cds mRNA 214. Influenza A virus 791 bp AY604827.1 (A/Taiwan/0572/2003(H3N2)) linear GI:50727534 hemagglutinin mRNA, partial cds mRNA 215. Influenza A virus 791 bp AY604821.1 (A/Taiwan/0578/2003(H3N2)) linear GI:50727522 hemagglutinin mRNA, partial cds mRNA 216. Influenza A virus 791 bp AY604820.1 (A/Taiwan/0583/2003(H3N2)) linear GI:50727520 hemagglutinin mRNA, partial cds mRNA 217. Influenza A virus 297 bp AY303722.1 (A/Taiwan/0646/2000 (H3N2)) linear GI:32330933 polymerase basic protein 1 (PB1) mRNA mRNA, partial cds 218. Influenza A virus 844 bp AY303723.1 (A/Taiwan/0646/2000 (H3N2)) linear GI:32330935 hemagglutinin (HA) mRNA, partial cds mRNA 219. Influenza A virus 844 bp AF362811.1 (A/human/Taiwan/0830/99(H3N2)) linear GI:15055122 hemagglutinin (HA) mRNA, partial cds mRNA 220. Influenza A virus 791 bp AY625731.1 (A/Taiwan/0964/2001(H3N2)) linear GI:50604469 hemagglutinin (HA) mRNA, partial cds mRNA 221. Influenza A virus 844 bp AF362812.1 (A/human/Taiwan/1008/99(H3N2)) linear GI:15055124 hemagglutinin (HA) mRNA, partial cds mRNA 222. Influenza A virus 297 bp AY303725.1 (A/Taiwan/1008/99 (H3N2)) polymerase linear GI:32330939 basic protein 1 (PB1) mRNA, partial mRNA cds 223. Influenza A virus 750 bp EU068138.1 (A/Taiwan/1219/2004(H3N2)) linear GI:158452149 hemagglutinin (HA) mRNA, partial cds mRNA 224. Influenza A virus 750 bp EU068125.1 (A/Taiwan/1315/2005(H3N2)) linear GI:158452123 hemagglutinin (HA) mRNA, partial cds mRNA 225. Influenza A virus 750 bp EU068153.1 (A/Taiwan/1511/2004(H3N2)) linear GI:158452179 hemagglutinin (HA) mRNA, partial cds mRNA 226. Influenza A virus 750 bp EU068119.1 (A/Taiwan/1533/2003(H3N2)) linear GI:158452111 hemagglutinin (HA) mRNA, partial cds mRNA 227. Influenza A virus 844 bp AF362813.1 (A/human/Taiwan/1537/99(H3N2)) linear GI :15055126 hemagglutinin (HA) mRNA, partial cds mRNA 228. Influenza A virus 297 bp AY303728.1 (A/Taiwan/1537/99 (H3N2)) polymerase linear GI:32330945 basic protein 1 (PB1) mRNA, partial mRNA cds 229. Influenza A virus 791 bp AY604826.1 (A/Taiwan/1566/2003(H3N2)) linear GI:50727532 hemagglutinin mRNA, partial cds mRNA 230. Influenza A virus 791 bp AY604819.1 (A/Taiwan/1568/2003(H3N2)) linear GI:50727518 hemagglutinin mRNA, partial cds mRNA 231. Influenza A virus 750 bp EU068116.1 (A/Taiwan/158/2003(H3N2)) linear GI:158452105 hemagglutinin (HA) mRNA, partial cds mRNA 232. Influenza A virus 875 bp AF138709.2 (A/Taiwan/1600/96(H3N2)) matrix linear GI:4996869 protein M1 (M) mRNA, partial cds mRNA 233. Influenza A virus 750 bp EU068117.1 (A/Taiwan/1613/2003(H3N2)) linear GI:158452107 hemagglutinin (HA) mRNA, partial cds mRNA 234. Influenza A virus 750 bp EU068148.1 (A/Taiwan/1651/2004(H3N2)) linear GI:158452169 hemagglutinin (HA) mRNA, partial cds mRNA 235. Influenza A virus 844 bp AF362814.1 (A/human/Taiwan/1748/97(H3N2)) linear GI:15055128 hemagglutinin (HA) mRNA, partial cds mRNA 236. Influenza A virus 297 bp AY303729.1 (A/Taiwan/1748/97 (H3N2)) polymerase linear GI:32330947 basic protein 1 (PB1) mRNA, partial mRNA cds 237. Influenza A virus 872 bp AF138707.2 (A/Taiwan/179/96(H3N2)) matrix linear GI:4996865 protein M1 (M) mRNA, partial cds mRNA 238. Influenza A virus 750 bp EU068139.1 (A/Taiwan/1817/2004(H3N2)) linear GI:158452151 hemagglutinin (HA) mRNA, partial cds mRNA 239. Influenza A virus 750 bp EU068154.1 (A/Taiwan/1904/2003(H3N2)) linear GI:158452181 hemagglutinin (HA) mRNA, partial cds mRNA 240. Influenza A virus 750 bp EU068155.1 (A/Taiwan/1921/2003(H3N2)) linear GI:158452183 hemagglutinin (HA) mRNA, partial cds mRNA 241. Influenza A virus 844 bp AF362815.1 (A/human/Taiwan/1986/96(H3N2)) linear GI:15055130 hemagglutinin (HA) mRNA, partial cds mRNA 242. Influenza A virus 297 bp AY303730.1 (A/Taiwan/1990/96 (H3N2)) polymerase linear GI:32330949 basic protein 1 (PB1) mRNA, partial mRNA cds 243. Influenza A virus 844 bp AY303731.1 (A/Taiwan/1990/96 (H3N2)) linear GI:32330951 hemagglutinin (HA) mRNA, partial cds mRNA 244. Influenza A virus 861 bp AF139938.1 (A/Taiwan/20/98(H3N2)) H3 linear GI:4972940 hemagglutinin (HA) mRNA, partial cds mRNA 245. Influenza A virus 392 bp AF140627.1 (A/Taiwan/20/98(H3N2)) N2 linear GI :4972988 neuraminidase (NA) mRNA, partial cds mRNA 246. Influenza A virus 875 bp AF138715.2 (A/Taiwan/20/98(H3N2)) matrix linear GI:4996879 protein M1 (M) mRNA, partial cds mRNA 247. Influenza A virus 844 bp AF362816.1 (A/human/Taiwan/2031/97(H3N2)) linear GI:15055132 hemagglutinin (HA) mRNA, partial cds mRNA 248. Influenza A virus 861 bp AF139937.1 (A/Taiwan/2034/96(H3N2)) H3 linear GI:4972938 hemagglutinin (HA) mRNA, partial cds mRNA 340. Influenza A virus 1,701 bp EU021274.1 (A/Thailand/CU228/2006(H3N2)) linear GI:154224785 hemagglutinin (HA) mRNA, complete mRNA cds 341. Influenza A virus 1,347 bp EU021267.1 (A/Thailand/CU23/2006(H3N2)) linear GI:154224706 neuraminidase (NA) mRNA, partial cds mRNA 342. Influenza A virus 1,701 bp EU021266.1 (A/Thailand/CU23/2006(H3N2)) linear GI:154224777 hemagglutinin (HA) mRNA, complete mRNA cds 343. Influenza A virus 1,410 bp EU021283.1 (A/Thailand/CU231/2006(H3N2)) linear GI:154224722 neuraminidase (NA) mRNA, complete mRNA cds 344. Influenza A virus 1,701 bp EU021282.1 (A/Thailand/CU231/2006(H3N2)) linear GI:154224793 hemagglutinin (HA) mRNA, complete mRNA cds 345. Influenza A virus 1,410 bp EU021279.1 (A/Thailand/CU259/2006(H3N2)) linear GI:154224718 neuraminidase (NA) mRNA, complete mRNA cds 346. Influenza A virus 1,701 bp EU021278.1 (A/Thailand/CU259/2006(H3N2)) linear GI:154224789 hemagglutinin (HA) mRNA, complete mRNA cds 347. Influenza A virus 1,410 bp EU021281.1 (A/Thailand/CU260/2006(H3N2)) linear GI:154224720 neuraminidase (NA) mRNA, complete mRNA cds 348. Influenza A virus 1,129 bp EU021280.1 (A/Thailand/CU260/2006(H3N2)) linear GI:154224791 hemagglutinin (HA) mRNA, partial cds mRNA 349. Influenza A virus 1,410 bp EU021271.1 (A/Thailand/CU272/2007(H3N2)) linear GI:154224710 neuraminidase (NA) mRNA, complete mRNA cds 350. Influenza A virus 1,701 bp EU021270.1 (A/Thailand/CU272/2007(H3N2)) linear GI:154224781 hemagglutinin (HA) mRNA, complete mRNA cds 351. Influenza A virus 1,410 bp EU021273.1 (A/Thailand/CU280/2007(H3N2)) linear GI:154224712 neuraminidase (NA) mRNA, complete mRNA cds 352. Influenza A virus 1,701 bp EU021272.1 (A/Thailand/CU280/2007(H3N2)) linear GI:154224783 hemagglutinin (HA) mRNA, complete mRNA cds 353. Influenza A virus 1,410 bp EU021277.1 (A/Thailand/CU282/2007(H3N2)) linear GI:154224716 neuraminidase (NA) mRNA, complete mRNA cds 249. Influenza A virus 392 bp AF140620.1 (A/Taiwan/2034/96(H3N2)) N2 linear GI:4972974 neuraminidase (NA) mRNA, partial cds mRNA 250. Influenza A virus 297 bp AY303732.1 (A/Taiwan/2034/96(H3N2)) polymerase linear GI:32330953 basic protein 1 (PB1) mRNA, partial mRNA cds 251. Influenza A virus 791 bp AY604818.1 (A/Taiwan/2040/2003(H3N2)) linear GI:50727516 hemagglutinin mRNA, partial cds mRNA 252. Influenza A virus 750 bp EU068131.1 (A/Taiwan/2072/2006(H3N2)) linear GI:158452135 hemagglutinin (HA) mRNA, partial cds mRNA 253. Influenza A virus 861 bp AF139934.1 (A/Taiwan/21/98(H3N2)) H3 linear GI:4972932 hemagglutinin (HA) mRNA, partial cds mRNA 254. Influenza A virus 392 bp AF140624.1 (A/Taiwan/21/98(H3N2)) N2 linear GI:4972982 neuraminidase (NA) mRNA, partial cds mRNA 255. Influenza A virus 875 bp AF138716.2 (A/Taiwan/21/98(H3N2)) matrix linear GI:4996881 protein M1 (M) mRNA, partial cds mRNA 256. Influenza A virus 861 bp AF139932.1 (A/Taiwan/2191/96(H3N2)) H3 linear GI:4972928 hemagglutinin (HA) mRNA, partial cds mRNA 257. Influenza A virus 392 bp AF140622.1 (A/Taiwan/2191/96(H3N2)) N2 linear GI:4972978 neuraminidase (NA) mRNA, partial cds mRNA 258. Influenza A virus 875 bp AF138711.3 (A/Taiwan/2191/96(H3N2)) matrix linear GI:156147502 protein M1 (M) mRNA, partial cds mRNA 259. Influenza A virus 861 bp AF139936.1 (A/Taiwan/2192/96(H3N2)) H3 linear GI:4972936 hemagglutinin (HA) mRNA, partial cds mRNA 260. Influenza A virus 392 bp AF140626.1 (A/Taiwan/2192/96(H3N2)) N2 linear GI:4972986 neuraminidase (NA) mRNA, partial cds mRNA 261. Influenza A virus 297 bp AY303735.1 (A/Taiwan/2195/96 (H3N2)) polymerase linear GI:32330959 basic protein 1 (PB1) mRNA, partial mRNA cds 262. Influenza A virus 844 bp AY303736.1 (A/Taiwan/2195/96 (H3N2)) linear GI:32330961 hemagglutinin (HA) mRNA, partial cds mRNA 263. Influenza A virus 875 bp AF138718.2 (A/Taiwan/224/98(H3N2)) matrix linear GI:4996885 protein M1 (M) mRNA, partial cds mRNA 264. Influenza A virus 844 bp AF362817.1 (A/human/Taiwan/2548/99(H3N2)) linear GI:15055134 hemagglutinin (HA) mRNA, partial cds mRNA 265. Influenza A virus 750 bp EU068120.1 (A/Taiwan/268/2005(H3N2)) linear GI:158452113 hemagglutinin (HA) mRNA, partial cds mRNA 266. Influenza A virus 750 bp EU068149.1 (A/Taiwan/3008/2004(H3N2)) linear GI:158452171 hemagglutinin (HA) mRNA, partial cds mRNA 267. Influenza A virus 750 bp EU068152.1 (A/Taiwan/3075/2003(H3N2)) linear GI:158452177 hemagglutinin (HA) mRNA, partial cds mRNA 268. Influenza A virus 940 bp AF362818.1 (A/human/Taiwan/3083/00(H3N2)) linear GI:15055136 hemagglutinin (HA) mRNA, partial cds mRNA 269. Influenza A virus 791 bp AY604811.1 (A/Taiwan/3131/2002(H3N2)) linear GI:50727502 hemagglutinin mRNA, partial cds mRNA 270. Influenza A virus 750 bp EU068145.1 (A/Taiwan/3154/2004(H3N2)) linear GI:158452163 hemagglutinin (HA) mRNA, partial cds mRNA 271. Influenza A virus 750 bp EU068141.1 (A/Taiwan/3187/2004(H3N2)) linear GI:158452155 hemagglutinin (HA) mRNA, partial cds mRNA 272. Influenza A virus 750 bp EU068134.1 (A/Taiwan/3245/2004(H3N2)) linear GI:158452141 hemagglutinin (HA) mRNA, partial cds mRNA 273. Influenza A virus 750 bp EU068133.1 (A/Taiwan/3294/2005(H3N2)) linear GI:158452139 hemagglutinin (HA) mRNA, partial cds mRNA 274. Influenza A virus 861 bp AF139935.1 (A/Taiwan/3351/97(H3N2)) H3 linear GI:4972934 hemagglutinin (HA) mRNA, partial cds mRNA 275. Influenza A virus 392 bp AF140625.1 (A/Taiwan/3351/97(H3N2)) N2 linear GI:4972984 neuraminidase (NA) mRNA, partial cds mRNA 276. Influenza A virus 875 bp AF138713.2 (A/Taiwan/3351/97(H3N2)) matrix linear GI:4996875 protein M1 (M) mRNA, partial cds mRNA 277. Influenza A virus 297 bp AY303738.1 (A/Taiwan/3351/97(H3N2)) polymerase linear GI:32330965 basic protein 1 (PB1) mRNA, partial mRNA cds 278. Influenza A virus 750 bp EU068132.1 (A/Taiwan/3387/2005(H3N2)) linear GI:158452137 hemagglutinin (HA) mRNA, partial cds mRNA 279. Influenza A virus 297 bp AY303742.1 (A/Taiwan/3396/97 (H3N2)) polymerase linear GI:32330973 basic protein 1 (PB1) mRNA, partial mRNA cds 280. Influenza A virus 844 bp AY303743.1 (A/Taiwan/3396/97 (H3N2)) linear GI:32330975 hemagglutinin (HA) mRNA, partial cds mRNA 281. Influenza A virus 861 bp AF139930.1 (A/Taiwan/3427/97(H3N2)) H3 linear GI:4972924 hemagglutinin (HA) mRNA, partial cds mRNA 282. Influenza A virus 392 bp AF140619.1 (A/Taiwan/3427/97(H3N2)) N2 linear GI:4972972 neuraminidase (NA) mRNA, partial cds mRNA 283. Influenza A virus 861 bp AF139940.1 (A/Taiwan/346/98(H3N2)) H3 linear GI:4972944 hemagglutinin (HA) mRNA, partial cds mRNA 284. Influenza A virus 392 bp AF140787.1 (A/Taiwan/346/98(H3N2)) N2 linear GI:4972992 neuraminidase (NA) mRNA, partial cds mRNA 285. Influenza A virus 875 bp AF138719.2 (A/Taiwan/346/98(H3N2)) matrix linear GI:4996887 protein M1 (M) mRNA, partial cds mRNA 286. Influenza A virus 942 bp AF362819.1 (A/human/Taiwan/3460/00(H3N2)) linear GI:15055138 truncated hemagglutinin (HA) mRNA, mRNA partial cds 287. Influenza A virus 861 bp AF139933.1 (A/Taiwan/3469/97(H3N2)) H3 linear GI:4972930 hemagglutinin (HA) mRNA, partial cds mRNA 288. Influenza A virus 392 bp AF140623.1 (A/Taiwan/3469/97(H3N2)) N2 linear GI:4972980 neuraminidase (NA) mRNA, partial cds mRNA 289. Influenza A virus 875 bp AF138714.2 (A/Taiwan/3469/97(H3N2)) matrix linear GI:4996877 protein M1 (M) mRNA, partial cds mRNA 290. Influenza A virus 297 bp AY303744.1 (A/Taiwan/3503/97 (H3N2)) polymerase linear GI:32330977 basic protein 1 (PB1) mRNA, partial mRNA cds 291. Influenza A virus 844 bp AY303745.1 (A/Taiwan/3503/97 (H3N2)) linear GI:32330979 hemagglutinin (HA) mRNA, partial cds mRNA 292. Influenza A virus 919 bp AF138712.1 (A/Taiwan/3513/96(H3N2)) matrix linear GI:4928900 protein M1 (M) mRNA, partial cds mRNA 293. Influenza A virus 861 bp AF139931.1 (A/Taiwan/3513/97(H3N2)) H3 linear GI:4972926 hemagglutinin (HA) mRNA, partial cds mRNA 294. Influenza A virus 392 bp AF140621.1 (A/Taiwan/3513/97(H3N2)) N2 linear GI:4972976 neuraminidase (NA) mRNA, partial cds mRNA 295. Influenza A virus 791 bp AY604814.1 (A/Taiwan/3744/2002(H3N2)) linear GI:50727508 hemagglutinin mRNA, partial cds mRNA 296. Influenza A virus 940 bp AF362804.1 (A/human/Taiwan/3760/00(H3N2)) linear GI:15055108 hemagglutinin (HA) mRNA, partial cds mRNA 297. Influenza A virus 561 bp AY303747.1 (A/Taiwan/3896/2001 (H1N1)) linear GI:32330983 hemagglutinin (HA) mRNA, partial cds mRNA 298. Influenza A virus 791 bp AY604825.1 (A/Taiwan/4050/2003(H3N2)) linear GI:50727530 hemagglutinin mRNA, partial cds mRNA 299. Influenza A virus 791 bp AY604824.1 (A/Taiwan/4063/2003(H3N2)) linear GI:50727528 hemagglutinin mRNA, partial cds mRNA 300. Influenza A virus 750 bp EU068137.1 (A/Taiwan/41/2004(H3N2)) linear GI:158452147 hemagglutinin (HA) mRNA, partial cds mRNA 301. Influenza A virus 861 bp AF139939.1 (A/Taiwan/45/98(H3N2)) H3 linear GI:4972942 hemagglutinin (HA) mRNA, partial cds mRNA 302. Influenza A virus 392 bp AF140628.1 (A/Taiwan/45/98(H3N2)) N2 linear GI:4972990 neuraminidase (NA) mRNA, partial cds mRNA 303. Influenza A virus 875 bp AF138717.2 (A/Taiwan/45/98(H3N2)) matrix linear GI:4996883 protein M1 (M) mRNA, partial cds mRNA 304. Influenza A virus 750 bp EU068114.1 (A/Taiwan/4548/2003(H3N2)) linear GI:158452101 hemagglutinin (HA) mRNA, partial cds mRNA 305. Influenza A virus 791 bp AY604813.1 (A/Taiwan/4673/2002(H3N2)) linear GI:50727506 hemagglutinin mRNA, partial cds mRNA 306. Influenza A virus 791 bp AY604812.1 (A/Taiwan/4680/2002(H3N2)) linear GI:50727504 hemagglutinin mRNA, partial cds mRNA 307. Influenza A virus 750 bp EU068136.1 (A/Taiwan/4735/2004(H3N2)) linear GI:158452145 hemagglutinin (HA) mRNA, partial cds mRNA 308. Influenza A virus 750 bp EU068142.1 (A/Taiwan/4829/2005(H3N2)) linear GI:158452157 hemagglutinin (HA) mRNA, partial cds mRNA 309. Influenza A virus 750 bp EU068130.1 (A/Taiwan/4836/2005(H3N2)) linear GI:158452133 hemagglutinin (HA) mRNA, partial cds mRNA 310. Influenza A virus 750 bp EU068143.1 (A/Taiwan/4865/2005(H3N2)) linear GI:158452159 hemagglutinin (HA) mRNA, partial cds mRNA 311. Influenza A virus 750 bp EU068121.1 (A/Taiwan/4883/2005(H3N2)) linear GI:158452115 hemagglutinin (HA) mRNA, partial cds mRNA 312. Influenza A virus 791 bp AY604809.1 (A/Taiwan/4938/2002(H3N2)) linear GI:50727498 hemagglutinin mRNA, partial cds mRNA 313. Influenza A virus 791 bp AY604815.1 (A/Taiwan/4954/2002(H3N2)) linear GI:50727510 hemagglutinin mRNA, partial cds mRNA 314. Influenza A virus 791 bp AY604810.1 (A/Taiwan/4963/2002(H3N2)) linear GI:50727500 hemagglutinin mRNA, partial cds mRNA 315. Influenza A virus 750 bp EU068122.1 (A/Taiwan/4987/2005(H3N2)) linear GI:158452117 hemagglutinin (HA) mRNA, partial cds mRNA 316. Influenza A virus 750 bp EU068127.1 (A/Taiwan/4990/2005(H3N2)) linear GI:158452127 hemagglutinin (HA) mRNA, partial cds mRNA 317. Influenza A virus 750 bp EU068118.1 (A/Taiwan/5/2003(H3N2)) linear GI:158452109 hemagglutinin (HA) mRNA, partial cds mRNA 318. Influenza A virus 791 bp AY604816.1 (A/Taiwan/5153/2002(H3N2)) linear GI:50727512 hemagglutinin mRNA, partial cds mRNA 319. Influenza A virus 750 bp EU068128.1 (A/Taiwan/5267/2005(H3N2)) linear GI:158452129 hemagglutinin (HA) mRNA, partial cds mRNA 320. Influenza A virus 750 bp EU068146.1 (A/Taiwan/556/2004(H3N2)) linear GI :158452165 hemagglutinin (HA) mRNA, partial cds mRNA 321. Influenza A virus 750 bp EU068126.1 (A/Taiwan/5694/2005(H3N2)) linear GI:158452125 hemagglutinin (HA) mRNA, partial cds mRNA 322. Influenza A virus 750 bp EU068147.1 (A/Taiwan/587/2004(H3N2)) linear GI:158452167 hemagglutinin (HA) mRNA, partial cds mRNA 323. Influenza A virus 750 bp EU068151.1 (A/Taiwan/592/2004(H3N2)) linear GI:158452175 hemagglutinin (HA) mRNA, partial cds mRNA 324. Influenza A virus 791 bp AY604829.1 (A/Taiwan/7099/2003(H3N2)) linear GI:50727538 hemagglutinin mRNA, partial cds mRNA 325. Influenza A virus 791 bp AY604830.1 (A/Taiwan/7100/2003(H3N2)) linear GI:50727540 hemagglutinin mRNA, partial cds mRNA 326. Influenza A virus 750 bp EU068150.1 (A/Taiwan/7196/2003(H3N2)) linear GI:158452173 hemagglutinin (HA) mRNA, partial cds mRNA 327. Influenza A virus 750 bp EU068135.1 (A/Taiwan/7568/2004(H3N2)) linear GI:158452143 hemagglutinin (HA) mRNA, partial cds mRNA 328. Influenza A virus 750 bp EU068144.1 (A/Taiwan/7601/2005(H3N2)) linear GI:158452161 hemagglutinin (HA) mRNA, partial cds mRNA 329. Influenza A virus 750 bp EU068124.1 (A/Taiwan/7681/2005(H3N2)) linear GI:158452121 hemagglutinin (HA) mRNA, partial cds mRNA 330. Influenza A virus 750 bp EU068123.1 (A/Taiwan/7702/2005(H3N2)) linear GI:158452119 hemagglutinin (HA) mRNA, partial cds mRNA 331. Influenza A virus 750 bp EU068129.1 (A/Taiwan/7873/2005(H3N2)) linear GI:158452131 hemagglutinin (HA) mRNA, partial cds mRNA 332. Influenza A virus 750 bp EU068115.1 (A/Taiwan/8/2003(H3N2)) linear GI:158452103 hemagglutinin (HA) mRNA, partial cds mRNA 333. Influenza A virus 750 bp EU068140.1 (A/Taiwan/93/2004(H3N2)) linear GI:158452153 hemagglutinin (HA) mRNA, partial cds mRNA 334. Influenza A virus 528 bp AY962016.1 (A/Taoyuan/108/02(H3N2)) linear GI:68138189 hemagglutinin (HA) mRNA, partial cds mRNA 335. Influenza A virus 754 bp AY973338.1 (A/Taoyuan/108/02(H3N2)) linear GI:70673232 neuraminidase (NA) mRNA, partial cds mRNA 336. Influenza A virus 882 bp AY986998.1 (A/Taoyuan/108/02(H3N2)) linear GI:70728123 nucleoprotein (NP) mRNA, partial cds mRNA 337. Influenza A virus 1,410 bp EU021285.1 (A/Thailand/CU124/2006(H3N2)) linear GI:154224724 neuraminidase (NA) mRNA, complete mRNA cds 338. Influenza A virus 1,701 bp EU021284.1 (A/Thailand/CU124/2006(H3N2)) linear GI:154224795 hemagglutinin (HA) mRNA, complete mRNA cds 339. Influenza A virus 1,410 bp EU021275.1 (A/Thailand/CU228/2006(H3N2)) linear GI:154224714 neuraminidase (NA) mRNA, complete mRNA cds 354. Influenza A virus 1,701 bp EU021276.1 (A/Thailand/CU282/2007(H3N2)) linear GI:154224787 hemagglutinin (HA) mRNA, complete mRNA cds 355. Influenza A virus 1,413 bp EU021265.1 (A/Thailand/CU32/2006(H1N1)) linear GI:154224704 neuraminidase (NA) mRNA, complete mRNA cds 361. Influenza A virus 1,410 bp EU021269.1 (A/Thailand/CU46/2006(H3N2)) linear GI:154224708 neuraminidase (NA) mRNA, complete mRNA cds 362. Influenza A virus 1,701 bp EU021268.1 (A/Thailand/CU46/2006(H3N2)) linear GI:154224779 hemagglutinin (HA) mRNA, complete mRNA cds 377. Influenza A virus 987 bp U77837.1 (A/Tottori/849AM1AL3/1994(H3N2)) linear GI:2992515 hemagglutinin (HA) mRNA, partial cds mRNA 378. Influenza A virus 987 bp U77833.1 (A/Tottori/849AM2/1994(H3N2)) linear GI:2992507 hemagglutinin (HA) mRNA, partial cds mRNA 379. Influenza A virus 987 bp U77839.1 (A/Tottori/849AM2AL3/1994(H3N2)) linear GI:2992519 hemagglutinin (HA) mRNA, partial cds mRNA 380. Influenza A virus 987 bp U77835.1 (A/Tottori/849AM4/1994(H3N2)) linear GI:2992511 hemagglutinin (HA) mRNA, partial cds mRNA 382. Influenza A virus 987 bp U77834.1 (A/Tottori/872AM2/1994(H3N2)) linear GI:2992509 hemagglutinin (HA) mRNA, partial cds mRNA 383. Influenza A virus 987 bp U77840.1 (A/Tottori/872AM2AL3/1994(H3N2)) linear GI:2992521 hemagglutinin (HA) mRNA, partial cds mRNA 384. Influenza A virus 987 bp U77836.1 (A/Tottori/872AM4/1994(H3N2)) linear GI:2992513 hemagglutinin (HA) mRNA, partial cds mRNA 385. Influenza A virus 987 bp U77832.1 (A/Tottori/872K4/1994(H3N2)) linear GI:2992505 hemagglutinin (HA) mRNA, partial cds mRNA 386. Influenza A virus (A/United 987 bp AF501529.1 Kingdom/26554/99(H3N2)) linear GI:21314314 hemagglutinin (HA) mRNA, partial cds mRNA 387. Influenza A virus (A/United 987 bp AF501527.1 Kingdom/34300/99(H3N2)) linear GI:21314310 hemagglutinin (HA) mRNA, partial cds mRNA 388. Influenza A virus 987 bp AF501533.1 (A/Utah/20997/99(H3N2)) linear GI:21314322 hemagglutinin (HA) mRNA, partial cds mRNA 389. Influenza A virus 1,565 bp AF072545.1 (A/Victoria/3/75) segment 5 linear GI:4218933 nucleoprotein mRNA, complete cds mRNA 390. Influenza A virus 1,762 bp AF017270.2 (A/Vienna/47/96M(H3N2)) linear GI:14286338 hemagglutinin (HA) mRNA, complete mRNA cds 391. Influenza A virus 1,762 bp AF017272.2 (A/Vienna/47/96V(H3N2)) linear GI:15004991 hemagglutinin (HA) mRNA, complete mRNA cds 392. Influenza A virus 1,069 bp AF017271.1 (A/Vienna/81/96V(H3N2)) linear GI:2407251 hemagglutinin (HA) mRNA, partial cds mRNA 393. Influenza A virus 987 bp AF501532.1 (A/Virginia/21712/99(H3N2)) linear GI:21314320 hemagglutinin (HA) mRNA, partial cds mRNA 394. Influenza A virus 987 bp AF501515.1 (A/Virginia/21716/99(H3N2)) linear GI:21314286 hemagglutinin (HA) mRNA, partial cds mRNA 395. Influenza A virus 987 bp AF501530.1 (A/Virginia/21735/99(H3N2)) linear GI:21314316 hemagglutinin (HA) mRNA, partial cds mRNA 396. Influenza A virus 987 bp AF501524.1 (A/Virginia/21743/99(H3N2)) linear GI:21314304 hemagglutinin (HA) mRNA, partial cds mRNA 397. Influenza A virus 987 bp AF501519.1 (A/Virginia/21754/99(H3N2)) linear GI:21314294 hemagglutinin (HA) mRNA, partial cds mRNA 398. Influenza A virus 987 bp AF501523.1 (A/Virginia/21799/99(H3N2)) linear GI:21314302 hemagglutinin (HA) mRNA, partial cds mRNA 399. Influenza A virus 987 bp AF501525.1 (A/Virginia/21817/99(H3N2)) linear GI:21314306 hemagglutinin (HA) mRNA, partial cds mRNA 400. Influenza A virus 987 bp AF501520.1 (A/Virginia/21822/99(H3N2)) linear GI:21314296 hemagglutinin (HA) mRNA, partial cds mRNA 401. Influenza A virus 987 bp AF501528.1 (A/Virginia/21828/99(H3N2)) linear GI:21314312 hemagglutinin (HA) mRNA, partial cds mRNA 402. Influenza A virus 987 bp AF501517.1 (A/Virginia/21833/99(H3N2)) linear GI:21314290 hemagglutinin (HA) mRNA, partial cds mRNA 403. Influenza A virus 987 bp AF501522.1 (A/Virginia/21845/99(H3N2)) linear GI:21314300 hemagglutinin (HA) mRNA, partial cds mRNA 404. Influenza A virus 987 bp AF501535.1 (A/Virginia/21847/99(H3N2)) linear GI:21314326 hemagglutinin (HA) mRNA, partial cds mRNA 405. Influenza A virus 987 bp AF501521.1 (A/Virginia/G1/99(H3N2)) linear GI:21314298 hemagglutinin (HA) mRNA, partial cds mRNA 406. Influenza A virus 755 bp AY973339.1 (A/Yilan/508/03(H3N2)) neuraminidase linear GI:70673234 (NA) mRNA, partial cds mRNA 407. Influenza A virus 882 bp AY986999.1 (A/Yilan/508/03(H3N2)) nucleoprotein linear GI:70728125 (NP) mRNA, partial cds mRNA 408. Influenza A virus 740 bp AY962015.1 (A/Yilan/513/03(H3N2)) hemagglutinin linear GI:68138187 (HA) mRNA, partial cds mRNA 409. Influenza A virus 396 bp AY973340.1 (A/Yilan/513/03(H3N2)) neuraminidase linear GI:70673236 (NA) mRNA, partial cds mRNA 410. Influenza A virus 882 bp AY987000.1 (A/Yilan/513/03(H3N2)) nucleoprotein linear GI:70728127 (NP) mRNA, partial cds mRNA 411. Influenza A virus 511 bp AY962010.1 (A/Yilan/515/03(H3N2)) hemagglutinin linear GI:68138177 (HA) mRNA, partial cds mRNA 412. Influenza A virus 394 bp AY973341.1 (A/Yilan/515/03(H3N2)) neuraminidase linear GI:70673238 (NA) mRNA, partial cds mRNA 413. Influenza A virus 882 bp AY987001.1 (A/Yilan/516/03(H3N2)) nucleoprotein linear GI:70728129 (NP) mRNA, partial cds mRNA 414. Influenza A virus 530 bp AY962006.1 (A/Yilan/518/03(H3N2)) hemagglutinin linear GI:68138169 (HA) mRNA, partial cds mRNA 415. Influenza A virus 397 bp AY973342.1 (A/Yilan/518/03(H3N2)) neuraminidase linear GI:70673240 (NA) mRNA, partial cds mRNA 416. Influenza A virus 882 bp AY987002.1 (A/Yilan/518/03(H3N2)) nucleoprotein linear GI:70728131 (NP) mRNA, partial cds mRNA 417. Influenza A virus 777 bp AY962002.1 (A/Yilan/538/04(H3N2)) hemagglutinin linear GI:68138161 (HA) mRNA, partial cds mRNA 418. Influenza A virus 783 bp AY973343.1 (A/Yilan/538/04(H3N2)) neuraminidase linear GI:70673242 (NA) mRNA, partial cds mRNA 419. Influenza A virus 882 bp AY987003.1 (A/Yilan/538/04(H3N2)) nucleoprotein linear GI:70728133 (NP) mRNA, partial cds mRNA 420. Influenza A virus 788 bp AY962003.1 (A/Yilan/549/04(H3N2)) hemagglutinin linear GI:68138163 (HA) mRNA, partial cds mRNA 421. Influenza A virus 779 bp AY973344.1 (A/Yilan/549/04(H3N2)) neuraminidase linear GI:70673244 (NA) mRNA, partial cds mRNA 422. Influenza A virus 882 bp AY987004.1 (A/Yilan/549/04(H3N2)) nucleoprotein linear GI:70728135 (NP) mRNA, partial cds mRNA 423. Influenza A virus 776 bp AY962013.1 (A/Yilan/557/04(H3N2)) hemagglutinin linear GI:68138183 (HA) mRNA, partial cds mRNA 424. Influenza A virus 796 bp AY973345.1 (A/Yilan/557/04(H3N2)) neuraminidase linear GI:70673246 (NA) mRNA, partial cds mRNA 425. Influenza A virus 882 bp AY987005.1 (A/Yilan/557/04(H3N2)) nucleoprotein linear GI:70728137 (NP) mRNA, partial cds mRNA 426. Influenza A virus 753 bp AY962014.1 (A/Yilan/566/04(H3N2)) hemagglutinin linear GI:68138185 (HA) mRNA, partial cds mRNA 427. Influenza A virus 808 bp AY973346.1 (A/Yilan/566/04(H3N2)) neuraminidase linear GI:70673248 (NA) mRNA, partial cds mRNA 428. Influenza A virus 882 bp AY987006.1 (A/Yilan/566/04(H3N2)) nucleoprotein linear GI:70728139 (NP) mRNA, partial cds mRNA 429. Influenza A virus 987 bp AY138513.1 (A/zhejiang/06/99(H3N2)) linear GI:24895131 hemagglutinin (HA) mRNA, partial cds mRNA 430. Influenza A virus 987 bp AY138515.1 (A/zhejiang/10/98(H3N2)) linear GI:24895149 hemagglutinin (HA) mRNA, partial cds mRNA 431. Influenza A virus 987 bp AY138516.1 (A/zhejiang/11/2002(H3N2)) linear GI:24895159 hemagglutinin (HA) mRNA, partial cds mRNA 432. Influenza A virus 987 bp AY138514.1 (A/zhejiang/12/99(H3N2)) linear GI:24895141 hemagglutinin-like (HA) mRNA, mRNA partial sequence 433. Influenza A virus 987 bp AY138519.1 (A/zhejiang/8/2002(H3N2)) linear GI:24895188 hemagglutinin (HA) mRNA, partial cds mRNA 434. Influenza A virus H3N2 strain 840 bp U65670.1 A/Akita/1/94 nonstructural protein 1 linear GI:3929405 and nonstructural protein 2 mRNAs, mRNA complete cds 435. Influenza A virus H3N2 strain 840 bp U65671.1 A/Akita/1/95 nonstructural protein 1 linear GI:3929408 and nonstructural protein 2 mRNAs, mRNA complete cds 436. Influenza A virus H3N2 strain 840 bp U65673.1 A/Shiga/20/95 nonstructural protein linear GI:3929411 1 and nonstructural protein 2 mRNAs, mRNA complete cds 437. Influenza A virus H3N2 strain 840 bp U65674.1 A/Miyagi/69/95 nonstructural protein linear GI:3929414 1 and nonstructural protein 2 mRNAs, mRNA complete cds 438. Influenza A virus H3N2 strain 840 bp U65672.1 A/Hebei/19/95 nonstructural protein linear GI:6468319 1 and nonstructural protein 2 mRNAs, mRNA complete cds A/Aichi/69/1994(H3N2) haemagglutinin U48446.1 A/Bangkok/1/1979 (H3N2) AF201843.1 hemagglutinin (HA) A/Beijing/353/89(H3) hemagglutinin U97740.1 (HA) A/Beijing/353/1989(H3N2) Z46391.1 haemagglutinin A/chicken/Singapore/2002(H3N2) M2 EU014143.1 protein A/Christ Hospita1/231/82(H3N2)) U77830.1 hemagglutinin (HA) A/duck/Eastern China/36/2002(H3N2) EU429701.1 segment 6 neuraminidase (NA) A/duck/Eastern China/160/2003(H3N2) EU429732.1 segment 6 neuraminidase (NA) A/duck/Eastern China/848/2003(H3N2) EU429721.1 segment 6 neuraminidase (NA) A/duck/Eastern China/770/2003(H3N2) EU429736.1 segment 6 neuraminidase (NA) A/duck/Eastern China/855/2003(H3N2) EU429737.1 segment 6 neuraminidase (NA) A/duck/Eastern China/875/2003(H3N2) EU429738.1 segment 6 neuraminidase (NA) A/duck/Eastern China/901/2003(H3N2) EU429739.1 segment 6 neuraminidase (NA) A/duck/Eastern China/866/2003(H3N2) EU429756.1 segment 6 neuraminidase (NA) A/duck/Eastern China/857/2003(H3N2) EU429761.1 segment 6 neuraminidase (NA) A/duck/Eastern China/852/2003(H3N2) EU429767.1 segment 6 neuraminidase (NA) A/duck/Eastern China/838/2003(H3N2) EU429720.1 segment 6 neuraminidase (NA) A/duck/Eastern China/6/2004(H3N2) EU429745.1 segment 6 neuraminidase (NA) A/duck/Eastern China/03/2005(H3N2) EU429781.1 segment 6 neuraminidase (NA) A/duck/Eastern China/02/2006(H3N2) EU429769.1 segment 6 neuraminidase (NA) A/duck/Eastern China/04/2006(H3N2) EU429770.1 segment 6 neuraminidase (NA) A/duck/Eastern China/21/2006(H3N2) EU429771.1 segment 6 neuraminidase (NA) A/duck/Eastern China/23/2006(H3N2) EU429772.1 segment 6 neuraminidase (NA) A/duck/Eastern China/31/2006(H3N2) EU429773.1 segment 6 neuraminidase (NA) A/duck/Eastern China/35/2006(H3N2) EU429768.1 segment 6 neuraminidase (NA) A/duck/Eastern China/42/2006(H3N2) EU429774.1 segment 6 neuraminidas (NA) A/duck/Eastern China/53/2006(H3N2) EU429775.1 segment 6 neuraminidase (NA) A/duck/Eastern China/60/2006(H3N2) EU429776.1 segment 6 neuraminidase (NA) A/duck/Eastern China/62/2006(H3N2) EU429784.1 segment 6 neuraminidase (NA) A/duck/Eastern China/63/2006(H3N2) EU429777.1 segment 6 neuraminidase (NA) A/duck/Eastern China/142/2006(H3N2) EU429742.1 segment 6 neuraminidase (NA) A/Dunedin/4/1973 (H3N2) AF201842.1 hemagglutinin (HA)

TABLE 8 Influenza H5N1 Antigens 1. Influenza A virus 827 bp AM503036.1 (A/chicken/Burkina linear GI:147846308 Faso/01.03/2006(H5N1)) mRNA for non- mRNA structural protein (ns gene) 2. Influenza A virus 990 bp AM503007.1 (A/chicken/Burkina linear GI:147846250 Faso/13.1/2006(H5N1)) partial mRNA mRNA for matrix protein 1 (m1 gene) 3. Influenza A virus 1,529 bp AM503029.1 (A/chicken/Burkina linear GI:147846294 Faso/13.1/2006(H5N1)) mRNA for mRNA nucleoprotein (np gene) 4. Influenza A virus 827 bp AM503037.1 (A/chicken/Burkina linear GI:147846310 Faso/13.1/2006(H5N1)) mRNA for non- mRNA structural protein (ns gene) 5. Influenza A virus 2,169 bp AM503046.1 (A/chicken/Burkina linear GI:147846328 Faso/13.1/2006(H5N1)) partial mRNA mRNA for polymerase (pa gene) 6. Influenza A virus 2,259 bp AM503056.1 (A/chicken/Burkina linear GI:147846348 Faso/13.1/2006(H5N1)) partial mRNA mRNA for polymerase basic protein 1 (pb1 gene) 7. Influenza A virus 2,315 bp AM503067.1 (A/chicken/Burkina linear GI:147846859 Faso/13.1/2006(H5N1)) partial mRNA mRNA for polymerase basic protein 2 (pb2 gene) 8. Influenza A virus 1,736 bp DQ023145.1 (A/chicken/China/1/02(H5N1)) linear GI:66775624 hemagglutinin (HA) mRNA, complete cds mRNA 9. Influenza A virus 1,509 bp DQ023146.1 (A/chicken/China/1/02(H5N1)) linear GI:66775626 nucleoprotein (NP) mRNA, complete cds mRNA 10. Influenza A virus 1,379 bp DQ023147.1 (A/chicken/China/1/02(H5N1)) linear GI:66775628 neuraminidase (NA) mRNA, complete cds mRNA 11. Influenza A virus 999 bp DQ650660.1 (A/chicken/Crimea/04/2005(H5N1)) linear GI:109692767 matrix protein (M) mRNA, complete cds mRNA 12. Influenza A virus 850 bp DQ650662.1 (A/chicken/Crimea/04/2005(H5N1)) linear GI:109692771 nonstructural protein (NS) mRNA, mRNA complete cds 13. Influenza A virus 994 bp DQ650664.1 (A/chicken/Crimea/08/2005(H5N1)) linear GI:109692775 matrix protein (M) mRNA, complete cds mRNA 14. Influenza A virus 1,532 bp DQ650666.1 (A/chicken/Crimea/08/2005(H5N1)) linear GI:109692779 nucleoprotein (NP) mRNA, complete cds mRNA 15. Influenza A virus 850 bp DQ650667.1 (A/chicken/Crimea/08/2005(H5N1)) linear GI:109692781 nonstructural protein (NS) mRNA, mRNA complete cds 16. Influenza A virus 2,208 bp DQ650668.1 (A/chicken/Crimea/08/2005(H5N1)) linear GI:109692783 polymerase acidic protein (PA) mRNA, mRNA complete cds 17. Influenza A virus 2,305 bp DQ650670.1 (A/chicken/Crimea/08/2005(H5N1)) linear GI:109692787 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 18. Influenza A virus 1,015 bp DQ676838.1 (A/chicken/Dovolnoe/03/2005(H5N1)) linear GI:108782527 hemagglutinin (HA) mRNA, partial cds mRNA 20. Influenza A virus 2,341 bp DQ366327.1 (A/chicken/Guangxi/12/2004(H5N1)) linear GI:86753731 polymerase PB2 mRNA, complete cds mRNA 21. Influenza A virus 2,341 bp DQ366328.1 (A/chicken/Guangxi/12/2004(H5N1)) linear GI:86753741 polymerase PB1 mRNA, complete cds mRNA 22. Influenza A virus 2,233 bp DQ366329.1 (A/chicken/Guangxi/12/2004(H5N1)) PA linear GI:86753751 protein mRNA, complete cds mRNA 23. Influenza A virus 1,565 bp DQ366331.1 (A/chicken/Guangxi/12/2004(H5N1)) linear GI:86753771 nucleocapsid mRNA, complete cds mRNA 24. Influenza A virus 1,027 bp DQ366333.1 (A/chicken/Guangxi/12/2004(H5N1)) linear GI:86753791 matrix protein mRNA, complete cds mRNA 25. Influenza A virus (A/chicken/Hong 1,718 bp AF057291.1 Kong/258/97(H5N1)) hemagglutinin linear GI:3068720 mRNA, complete cds mRNA 26. Influenza A virus (A/chicken/Hong 1,318 bp AF057292.1 Kong/258/97(H5N1)) neuraminidase linear GI:3068722 mRNA, partial cds mRNA 27. Influenza A virus (A/chicken/Hong 1,508 bp AF057293.1 Kong/258/97(H5N1)) nucleoprotein linear GI:3068724 mRNA, complete cds mRNA 28. Influenza A virus (A/Chicken/Hong 1,726 bp AF082034.1 Kong/728/97 (H5N1) hemagglutinin H5 linear GI:4240435 mRNA, complete cds mRNA 29. Influenza A virus (A/Chicken/Hong 1,726 bp AF082035.1 Kong/786/97 (H5N1)) hemagglutinin H5 linear GI:4240437 mRNA, complete cds mRNA 30. Influenza A virus (A/Chicken/Hong 1,726 bp AF082036.1 Kong/915/97(H5N1)) hemagglutinin H5 linear GI:4240439 mRNA, complete cds mRNA 31. Influenza A virus (A/Chicken/Hong 1,091 bp AF082037.1 Kong/990/97 (H5N1)) hemagglutinin H5 linear GI:4240441 mRNA, partial cds mRNA 32. Influenza A virus 1,002 bp DQ676835.1 (A/chicken/Krasnodar/01/2006(H5N1)) linear GI:108782521 matrix protein 1 (M) mRNA, complete mRNA cds 33. Influenza A virus 850 bp DQ676837.1 (A/chicken/Krasnodar/01/2006(H5N1)) linear GI:108782525 nonstructural protein (NS) mRNA, mRNA complete cds 34. Influenza A virus 1,754 bp DQ449632.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289625 hemagglutinin (HA) mRNA, complete cds mRNA 35. Influenza A virus 1,002 bp DQ449633.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289627 matrix protein 1 (M) mRNA, complete mRNA cds 36. Influenza A virus 1,373 bp DQ449634.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289629 neuraminidase (NA) mRNA, complete cds mRNA 37. Influenza A virus 1,540 bp DQ449635.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289631 nucleoprotein (NP) mRNA, complete cds mRNA 38. Influenza A virus 850 bp DQ449636.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289633 nonstructural protein (NS) mRNA, mRNA complete cds 39. Influenza A virus 2,208 bp DQ449637.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289635 polymerase acidic protein (PA) mRNA, mRNA complete cds 40. Influenza A virus 2,316 bp DQ449638.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289637 polymerase basic protein 1 (PB1) mRNA mRNA, complete cds 41. Influenza A virus 2,316 bp DQ449639.1 (A/chicken/Kurgan/05/2005(H5N1)) linear GI:90289646 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 42. Influenza A virus 184 bp EU447276.1 (A/chicken/Lobzenko/01/2008(H5N1)) linear GI:168998217 hemagglutinin (HA) mRNA, partial cds mRNA 43. Influenza A virus 1,002 bp DQ676831.1 (A/chicken/Mahachkala/05/2006(H5N1)) linear GI:108782513 matrix protein 1 (M) mRNA, complete mRNA cds 44. Influenza A virus 850 bp DQ676833.1 (A/chicken/Mahachkala/05/2006(H5N1)) linear GI:108782517 nonstructural protein (NS) mRNA, mRNA complete cds 45. Influenza A virus 1,531 bp AM503030.1 (A/chicken/Nigeria/AB13/2006(H5N1)) linear GI:147846296 mRNA for nucleoprotein (np gene) mRNA 46. Influenza A virus 827 bp AM503040.1 (A/chicken/Nigeria/AB13/2006(H5N1)) linear GI:147846316 mRNA for non-structural protein (ns mRNA gene) 47. Influenza A virus 2,169 bp AM503051.1 (A/chicken/Nigeria/AB13/2006(H5N1)) linear GI:147846338 partial mRNA for polymerase (pa gene) mRNA 48. Influenza A virus 2,259 bp AM503060.1 (A/chicken/Nigeria/AB13/2006(H5N1)) linear GI:147846845 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 49. Influenza A virus 2,315 bp AM503071.1 (A/chicken/Nigeria/AB13/2006(H5N1)) linear GI:147846867 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 70. Influenza A virus (A/Chicken/Hong 1,055 bp DQ250158.1 Kong/3123.1/2002(H5N1)) neuraminidase linear GI:82412012 (NA) mRNA, partial cds mRNA 75. Influenza A virus 1,754 bp DQ676834.1 (A/chicken/Krasnodar/01/2006(H5N1)) linear GI:108782519 hemagglutinin (HA) mRNA, complete cds mRNA 78. Influenza A virus 1,373 bp DQ676836.2 (A/chicken/Krasnodar/01/2006(H5N1)) linear GI:115520953 neuraminidase (NA) mRNA, complete cds mRNA 91. Influenza A virus 184 bp EU447276.1 (A/chicken/Lobzenko/01/2008(H5N1)) linear GI:168998217 hemagglutinin (HA) mRNA, partial cds mRNA 92. Influenza A virus 1,683 bp DQ676830.1 (A/chicken/Mahachkala/05/2006(H5N1)) linear GI:108782511 hemagglutinin (HA) mRNA, complete cds mRNA 94. Influenza A virus 1,373 bp DQ676832.1 (A/chicken/Mahachkala/05/2006(H5N1)) linear GI:108782515 neuraminidase (NA) mRNA, complete cds mRNA 96. Influenza A virus 433 bp DQ096567.1 (A/chicken/Malaysia/01/2004(H5N1)) linear GI:69145364 neuramidase (NA) mRNA, partial cds mRNA 97. Influenza A virus 1,722 bp AM503002.1 (A/chicken/Nigeria/AB13/2006(H5N1)) linear GI:147846240 partial mRNA for hemagglutinin (ha mRNA gene) 98. Influenza A virus 1,329 bp AM503020.1 (A/chicken/Nigeria/AB13/2006(H5N1)) linear GI:147846276 partial mRNA for neuraminidase (na mRNA gene) 105. Influenza A virus 1,719 bp AM503003.1 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:147846242 partial mRNA for hemagglutinin (ha mRNA gene) 106. Influenza A virus 953 bp AM503011.1 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:147846258 partial mRNA for matrix protein 1 (m1 mRNA gene) 107. Influenza A virus 1,343 bp AM503025.1 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:147846286 partial mRNA for neuraminidase (na mRNA gene) 108. Influenza A virus 827 bp AM503041.1 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:147846318 mRNA for non-structural protein (ns mRNA gene) 109. Influenza A virus 2,169 bp AM503054.1 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:147846344 partial mRNA for polymerase (pa gene) mRNA 110. Influenza A virus 2,259 bp AM503061.1 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:147846847 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 111. Influenza A virus 2,315 bp AM503072.1 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:147846869 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 112. Influenza A virus 1,548 bp AM503034.2 (A/chicken/Nigeria/AB14/2006(H5N1)) linear GI:149773117 mRNA for nucleoprotein (np gene) mRNA 113. Influenza A virus 1,342 bp AM503022.1 (A/chicken/Nigeria/BA210/2006(H5N1)) linear GI:147846280 partial mRNA for neuraminidase (na mRNA gene) 114. Influenza A virus 1,321 bp AM503021.1 (A/chicken/Nigeria/BA211/2006(H5N1)) linear GI:147846278 partial mRNA for neuraminidase (na mRNA gene) 115. Influenza A virus 2,315 bp AM503073.1 (A/chicken/Nigeria/BA211/2006(H5N1)) linear GI:147846871 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 116. Influenza A virus 1,717 bp AM503004.1 (A/chicken/Nigeria/FA4/2006(H5N1)) linear GI:147846244 partial mRNA for hemagglutinin (ha mRNA gene) 117. Influenza A virus 989 bp AM503013.1 (A/chicken/Nigeria/FA4/2006(H5N1)) linear GI:147846262 partial mRNA for matrix protein 1 (m1 mRNA gene) 118. Influenza A virus 1,321 bp AM503026.1 (A/chicken/Nigeria/FA4/2006(H5N1)) linear GI:147846288 partial mRNA for neuraminidase (na mRNA gene) 119. Influenza A virus 827 bp AM503045.1 (A/chicken/Nigeria/FA4/2006(H5N1)) linear GI:147846326 mRNA for non-structural protein (ns mRNA gene) 120. Influenza A virus 2,169 bp AM503055.1 (A/chicken/Nigeria/FA4/2006(H5N1)) linear GI:147846346 partial mRNA for polymerase (pa gene) mRNA 121. Influenza A virus 2,259 bp AM503064.1 (A/chicken/Nigeria/FA4/2006(H5N1)) linear GI:147846853 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 122. Influenza A virus 2,224 bp AM503074.1 (A/chicken/Nigeria/FA4/2006(H5N1)) linear GI:147846873 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 123. Influenza A virus 1,717 bp AM502998.1 (A/chicken/Nigeria/FA6/2006(H5N1)) linear GI:147846232 partial mRNA for hemagglutinin (ha mRNA gene) 124. Influenza A virus 965 bp AM503012.1 (A/chicken/Nigeria/FA6/2006(H5N1)) linear GI:147846260 partial mRNA for matrix protein 1 (m1 mRNA gene) 125. Influenza A virus 1,327 bp AM503023.1 (A/chicken/Nigeria/FA6/2006(H5N1)) linear GI:147846282 partial mRNA for neuraminidase (na mRNA gene) 126. Influenza A virus 1,543 bp AM503031.1 (A/chicken/Nigeria/FA6/2006(H5N1)) linear GI:147846298 mRNA for nucleoprotein (np gene) mRNA 127. Influenza A virus 2,169 bp AM503052.1 (A/chicken/Nigeria/FA6/2006(H5N1)) linear GI:147846340 partial mRNA for polymerase (pa gene) mRNA 128. Influenza A virus 2,259 bp AM503063.1 (A/chicken/Nigeria/FA6/2006(H5N1)) linear GI:147846851 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 129. Influenza A virus 1,710 bp AM502999.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846234 partial mRNA for hemagglutinin (ha mRNA gene) 130. Influenza A virus 1,001 bp AM503009.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846254 partial mRNA for matrix protein 1 (m1 mRNA gene) 131. Influenza A virus 1,331 bp AM503018.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846272 partial mRNA for neuraminidase (na mRNA gene) 132. Influenza A virus 1,531 bp AM503035.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846306 mRNA for nucleoprotein (np gene) mRNA 133. Influenza A virus 827 bp AM503042.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846320 mRNA for non-structural protein (ns mRNA gene) 134. Influenza A virus 2,169 bp AM503049.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846334 partial mRNA for polymerase (pa gene) mRNA 135. Influenza A virus 2,259 bp AM503057.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846350 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 136. Influenza A virus 2,315 bp AM503068.1 (A/chicken/Nigeria/FA7/2006(H5N1)) linear GI:147846861 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 137. Influenza A virus 1,714 bp AM503001.1 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:147846238 partial mRNA for hemagglutinin (ha mRNA gene) 138. Influenza A virus 990 bp AM503010.1 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:147846256 partial mRNA for matrix protein 1 (m1 mRNA gene) 139. Influenza A virus 1,332 bp AM503024.1 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:147846284 partial mRNA for neuraminidase (na mRNA gene) 140. Influenza A virus 827 bp AM503044.1 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:147846324 mRNA for non-structural protein (ns mRNA gene) 141. Influenza A virus 2,169 bp AM503053.1 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:147846342 partial mRNA for polymerase (pa gene) mRNA 142. Influenza A virus 2,259 bp AM503059.1 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:147846843 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 143. Influenza A virus 2,315 bp AM503069.1 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:147846863 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 144. Influenza A virus 1,550 bp AM503033.2 (A/chicken/Nigeria/IF10/2006(H5N1)) linear GI:149773115 mRNA for nucleoprotein (np gene) mRNA 145. Influenza A virus 1,719 bp AM503005.1 (A/chicken/Nigeria/0D8/2006(H5N1)) linear GI:147846246 partial mRNA for hemagglutinin (ha mRNA gene) 146. Influenza A virus 989 bp AM503014.1 (A/chicken/Nigeria/0D8/2006(H5N1)) linear GI:147846264 partial mRNA for matrix protein 1 (m1 mRNA gene) 147. Influenza A virus 1,720 bp AM503000.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846236 partial mRNA for hemagglutinin (ha mRNA gene) 148. Influenza A virus 988 bp AM503015.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846266 partial mRNA for matrix protein 1 (m1 mRNA gene) 149. Influenza A virus 1,330 bp AM503019.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846274 partial mRNA for neuraminidase (na mRNA gene) 150. Influenza A virus 1,531 bp AM503032.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846300 mRNA for nucleoprotein (np gene) mRNA 151. Influenza A virus 827 bp AM503043.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846322 mRNA for non-structural protein (ns mRNA gene) 152. Influenza A virus 2,169 bp AM503050.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846336 partial mRNA for polymerase (pa gene) mRNA 153. Influenza A virus 2,259 bp AM503058.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846841 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 154. Influenza A virus 2,315 bp AM503070.1 (A/chicken/Nigeria/0D9/2006(H5N1)) linear GI:147846865 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 155. Influenza A virus 1,768 bp X07869.1 (A/chicken/Scotland/59(H5N1)) mRNA linear GI:60482 for haemagglutinin precursor mRNA 156. Influenza A virus 1,445 bp AJ416625.1 (A/chicken/Scotland/59(H5N1)) N1 gene linear GI:39840717 for neuraminidase, genomic RNA mRNA 161. Influenza A virus 1,497 bp DQ208502.1 (A/chicken/zz/02/2004(H5N1)) linear GI:77158587 nucleoprotein mRNA, complete cds mRNA 162. Influenza A virus (A/common 1,707 bp EF110519.1 coot/Switzerland/V544/2006(H5N1)) linear GI:119394676 hemagglutinin (HA) gene, complete cds mRNA 163. Influenza A virus (A/domestic 1,735 bp EU190482.1 goose/Pavlodar/1/2005(H5N1)) linear GI:158516739 hemagglutinin (HA) mRNA, complete cds mRNA 164. Influenza A virus 1,401 bp EU429750.1 (A/duck/Eastern China/145/2003(H5N1)) linear GI:167859465 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 165. Influenza A virus 1,407 bp EU429731.1 (A/duck/Eastern China/150/2003(H5N1)) linear GI:167859427 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 166. Influenza A virus 1,398 bp EU429783.1 (A/duck/Eastern China/22/2005(H5N1)) linear GI:167859531 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 167. Influenza A virus 1,398 bp EU429747.1 (A/duck/Eastern China/304/2002(H5N1)) linear GI:167859459 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 168. Influenza A virus 1,401 bp EU429727.1 (A/duck/Eastern China/318/2002(H5N1)) linear GI:167859419 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 169. Influenza A virus 1,399 bp EU429778.1 (A/duck/Eastern China/37/2006(H5N1)) linear GI:167859521 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 170. Influenza A virus 1,398 bp EU429757.1 (A/duck/Eastern China/40/2005(H5N1)) linear GI:167859479 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 171. Influenza A virus 1,398 bp EU429779.1 (A/duck/Eastern China/48/2006(H5N1)) linear GI:167859523 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 172. Influenza A virus 1,398 bp EU429763.1 (A/duck/Eastern China/51/2005(H5N1)) linear GI:167859491 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 173. Influenza A virus 1,398 bp EU429758.1 (A/duck/Eastern China/54/2005(H5N1)) linear GI:167859481 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 174. Influenza A virus 1,398 bp EU429764.1 (A/duck/Eastern China/58/2005(H5N1)) linear GI:167859493 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 175. Influenza A virus 1,398 bp EU429759.1 (A/duck/Eastern China/59/2005(H5N1)) linear GI:167859483 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 176. Influenza A virus 1,398 bp EU429765.1 (A/duck/Eastern China/89/2005(H5N1)) linear GI:167859495 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 177. Influenza A virus 1,399 bp EU429785.1 (A/duck/Eastern China/89/2006(H5N1)) linear GI:167859535 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 178. Influenza A virus 1,398 bp EU429717.1 (A/duck/Eastern China/97/2001(H5N1)) linear GI:167859399 segment 6 neuraminidase (NA) mRNA, mRNA complete cds 179. Influenza A virus 2,281 bp AY585504.1 (A/duck/Fujian/01/2002(H5N1)) linear GI:47156226 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 180. Influenza A virus 760 bp AY585378.1 (A/duck/Fujian/01/2002(H5N1)) matrix linear GI:47156310 protein mRNA, complete cds mRNA 181. Influenza A virus 1,357 bp AY585399.1 (A/duck/Fujian/01/2002(H5N1)) linear GI:47156352 neuraminidase (NA) mRNA, complete cds mRNA 182. Influenza A virus 1,497 bp AY585420.1 (A/duck/Fujian/01/2002(H5N1)) linear GI:47156394 nucleoprotein (NP) mRNA, complete cds mRNA 183. Influenza A virus 686 bp AY585441.1 (A/duck/Fujian/01/2002(H5N1)) linear GI:47156436 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 184. Influenza A virus 2,281 bp AY585505.1 (A/duck/Fujian/13/2002(H5N1)) linear GI:47156228 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 185. Influenza A virus 761 bp AY585379.1 (A/duck/Fujian/13/2002(H5N1)) matrix linear GI:47156312 protein mRNA, complete cds mRNA 186. Influenza A virus 1,357 bp AY585400.1 (A/duck/Fujian/13/2002(H5N1)) linear GI:47156354 neuraminidase (NA) mRNA, complete cds mRNA 187. Influenza A virus 1,499 bp AY585421.1 (A/duck/Fujian/13/2002(H5N1)) linear GI:47156396 nucleoprotein (NP) mRNA, complete cds mRNA 188. Influenza A virus 685 bp AY585442.1 (A/duck/Fujian/13/2002(H5N1)) linear GI:47156438 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 189. Influenza A virus 2,281 bp AY585506.1 (A/duck/Fujian/17/2001(H5N1)) linear GI:47156230 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 190. Influenza A virus 759 bp AY585380.1 (A/duck/Fujian/17/2001(H5N1)) matrix linear GI:47156314 protein mRNA, complete cds mRNA 191. Influenza A virus 1,418 bp AY585401.1 (A/duck/Fujian/17/2001(H5N1)) linear GI:47156356 neuraminidase (NA) mRNA, complete cds mRNA 192. Influenza A virus 1,498 bp AY585422.1 (A/duck/Fujian/17/2001(H5N1)) linear GI:47156398 nucleoprotein (NP) mRNA, complete cds mRNA 193. Influenza A virus 686 bp AY585443.1 (A/duck/Fujian/17/2001(H5N1)) linear GI:47156440 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 194. Influenza A virus 2,281 bp AY585507.1 (A/duck/Fujian/19/2000(H5N1)) linear GI:47156232 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 195. Influenza A virus 760 bp AY585381.1 (A/duck/Fujian/19/2000(H5N1)) matrix linear GI:47156316 protein mRNA, complete cds mRNA 196. Influenza A virus 1,355 bp AY585402.1 (A/duck/Fujian/19/2000(H5N1)) linear GI:47156358 neuraminidase (NA) mRNA, complete cds mRNA 197. Influenza A virus 1,498 bp AY585423.1 (A/duck/Fujian/19/2000(H5N1)) linear GI:47156400 nucleoprotein (NP) mRNA, complete cds mRNA 198. Influenza A virus 687 bp AY585444.1 (A/duck/Fujian/19/2000(H5N1)) linear GI:47156442 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 199. Influenza A virus 2,281 bp AY585508.1 (A/duck/Guangdong/01/2001(H5N1)) linear GI:47156234 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 200. Influenza A virus 760 bp AY585382.1 (A/duck/Guangdong/01/2001(H5N1)) linear GI:47156318 matrix protein mRNA, complete cds mRNA 201. Influenza A virus 1,414 bp AY585403.1 (A/duck/Guangdong/01/2001(H5N1)) linear GI:47156360 neuraminidase (NA) mRNA, complete cds mRNA 202. Influenza A virus 1,497 bp AY585424.1 (A/duck/Guangdong/01/2001(H5N1)) linear GI:47156402 nucleoprotein (NP) mRNA, complete cds mRNA 203. Influenza A virus 687 bp AY585445.1 (A/duck/Guangdong/01/2001(H5N1)) linear GI:47156444 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 204. Influenza A virus 2,280 bp AY585509.1 (A/duck/Guangdong/07/2000(H5N1)) linear GI:47156236 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 205. Influenza A virus 759 bp AY585383.1 (A/duck/Guangdong/07/2000(H5N1)) linear GI:47156320 matrix protein mRNA, complete cds mRNA 206. Influenza A virus 1,417 bp AY585404.1 (A/duck/Guangdong/07/2000(H5N1)) linear GI:47156362 neuraminidase (NA) mRNA, complete cds mRNA 207. Influenza A virus 1,497 bp AY585425.1 (A/duck/Guangdong/07/2000(H5N1)) linear GI:47156404 nucleoprotein (NP) mRNA, complete cds mRNA 208. Influenza A virus 690 bp AY585446.1 (A/duck/Guangdong/07/2000(H5N1)) linear GI:47156446 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 209. Influenza A virus 2,281 bp AY585510.1 (A/duck/Guangdong/12/2000(H5N1)) linear GI:47156238 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 210. Influenza A virus 760 bp AY585384.1 (A/duck/Guangdong/12/2000(H5N1)) linear GI:47156322 matrix protein mRNA, complete cds mRNA 211. Influenza A virus 1,359 bp AY585405.1 (A/duck/Guangdong/12/2000(H5N1)) linear GI:47156364 neuraminidase (NA) mRNA, complete cds mRNA 212. Influenza A virus 1,498 bp AY585426.1 (A/duck/Guangdong/12/2000(H5N1)) linear GI:47156406 nucleoprotein (NP) mRNA, complete cds mRNA 213. Influenza A virus 685 bp AY585447.1 (A/duck/Guangdong/12/2000(H5N1)) linear GI:47156448 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 214. Influenza A virus 2,281 bp AY585511.1 (A/duck/Guangdong/22/2002(H5N1)) linear GI:47156240 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 215. Influenza A virus 760 bp AY585385.1 (A/duck/Guangdong/22/2002(H5N1)) linear GI:47156324 matrix protein mRNA, complete cds mRNA 216. Influenza A virus 1,412 bp AY585406.1 (A/duck/Guangdong/22/2002(H5N1)) linear GI:47156366 neuraminidase (NA) mRNA, complete cds mRNA 217. Influenza A virus 1,499 bp AY585427.1 (A/duck/Guangdong/22/2002(H5N1)) linear GI:47156408 nucleoprotein (NP) mRNA, complete cds mRNA 218. Influenza A virus 682 bp AY585448.1 (A/duck/Guangdong/22/2002(H5N1)) linear GI:47156450 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 219. Influenza A virus 2,281 bp AY585512.1 (A/duck/Guangdong/40/2000(H5N1)) linear GI:47156242 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 220. Influenza A virus 760 bp AY585386.1 (A/duck/Guangdong/40/2000(H5N1)) linear GI:47156326 matrix protein mRNA, complete cds mRNA 221. Influenza A virus 1,401 bp AY585407.1 (A/duck/Guangdong/40/2000(H5N1)) linear GI:47156368 neuraminidase (NA) mRNA, partial cds mRNA 222. Influenza A virus 1,499 bp AY585428.1 (A/duck/Guangdong/40/2000(H5N1)) linear GI:47156410 nucleoprotein (NP) mRNA, complete cds mRNA 223. Influenza A virus 689 bp AY585449.1 (A/duck/Guangdong/40/2000(H5N1)) linear GI:47156452 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 224. Influenza A virus 2,281 bp AY585513.1 (A/duck/Guangxi/07/1999(H5N1)) linear GI:47156244 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 225. Influenza A virus 760 bp AY585387.1 (A/duck/Guangxi/07/1999(H5N1)) matrix linear GI:47156328 protein mRNA, complete cds mRNA 226. Influenza A virus 1,421 bp AY585408.1 (A/duck/Guangxi/07/1999(H5N1)) linear GI:47156370 neuraminidase (NA) mRNA, complete cds mRNA 227. Influenza A virus 1,501 bp AY585429.1 (A/duck/Guangxi/07/1999(H5N1)) linear GI:47156412 nucleoprotein (NP) mRNA, complete cds mRNA 228. Influenza A virus 687 bp AY585450.1 (A/duck/Guangxi/07/1999(H5N1)) linear GI:47156454 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 229. Influenza A virus 875 bp DQ366342.1 (A/duck/Guangxi/13/2004(H5N1)) linear GI:86753723 nonstructural protein 1 mRNA, mRNA complete cds 230. Influenza A virus 2,341 bp DQ366335.1 (A/duck/Guangxi/13/2004(H5N1)) linear GI:86753733 polymerase PB2 mRNA, complete cds mRNA 231. Influenza A virus 2,341 bp DQ366336.1 (A/duck/Guangxi/13/2004(H5N1)) linear GI:86753743 polymerase PB1 mRNA, complete cds mRNA 232. Influenza A virus 2,233 bp DQ366337.1 (A/duck/Guangxi/13/2004(H5N1)) PA linear GI:86753753 protein mRNA, complete cds mRNA 233. Influenza A virus 1,776 bp DQ366338.1 (A/duck/Guangxi/13/2004(H5N1)) linear GI:86753763 hemagglutinin mRNA, complete cds mRNA 234. Influenza A virus 1,565 bp DQ366339.1 (A/duck/Guangxi/13/2004(H5N1)) linear GI:86753773 nucleocapsid mRNA, complete cds mRNA 235. Influenza A virus 1,378 bp DQ366340.1 (A/duck/Guangxi/13/2004(H5N1)) linear GI:86753783 neuraminidase mRNA, complete cds mRNA 236. Influenza A virus 1,027 bp DQ366341.1 (A/duck/Guangxi/13/2004(H5N1)) matrix linear GI:86753793 protein mRNA, complete cds mRNA 237. Influenza A virus 2,281 bp AY585514.1 (A/duck/Guangxi/22/2001(H5N1)) linear GI:47156246 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 238. Influenza A virus 757 bp AY585388.1 (A/duck/Guangxi/22/2001(H5N1)) matrix linear GI:47156330 protein mRNA, partial cds mRNA 239. Influenza A virus 1,414 bp AY585409.1 (A/duck/Guangxi/22/2001(H5N1)) linear GI:47156372 neuraminidase (NA) mRNA, complete cds mRNA 240. Influenza A virus 1,498 bp AY585430.1 (A/duck/Guangxi/22/2001(H5N1)) linear GI:47156414 nucleoprotein (NP) mRNA, complete cds mRNA 241. Influenza A virus 687 bp AY585451.1 (A/duck/Guangxi/22/2001(H5N1)) linear GI:47156456 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 242. Influenza A virus 2,281 bp AY585515.1 (A/duck/Guangxi/35/2001(H5N1)) linear GI:47156248 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 243. Influenza A virus 760 bp AY585389.1 (A/duck/Guangxi/35/2001(H5N1)) matrix linear GI:47156332 protein mRNA, complete cds mRNA 244. Influenza A virus 1,414 bp AY585410.1 (A/duck/Guangxi/35/2001(H5N1)) linear GI:47156374 neuraminidase (NA) mRNA, complete cds mRNA 245. Influenza A virus 1,498 bp AY585431.1 (A/duck/Guangxi/35/2001(H5N1)) linear GI:47156416 nucleoprotein (NP) mRNA, complete cds mRNA 246. Influenza A virus 685 bp AY585452.1 (A/duck/Guangxi/35/2001(H5N1)) linear GI:47156458 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 247. Influenza A virus 2,281 bp AY585516.1 (A/duck/Guangxi/50/2001(H5N1)) linear GI:47156250 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 248. Influenza A virus 760 bp AY585398.1 (A/duck/Guangxi/50/2001(H5N1)) matrix linear GI:47156350 protein mRNA, complete cds mRNA 249. Influenza A virus 1,354 bp AY585411.1 (A/duck/Guangxi/50/2001(H5N1)) linear GI:47156376 neuraminidase (NA) mRNA, complete cds mRNA 250. Influenza A virus 1,498 bp AY585432.1 (A/duck/Guangxi/50/2001(H5N1)) linear GI:47156418 nucleoprotein (NP) mRNA, complete cds mRNA 251. Influenza A virus 686 bp AY585453.1 (A/duck/Guangxi/50/2001(H5N1)) linear GI:47156460 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 252. Influenza A virus 2,281 bp AY585517.1 (A/duck/Guangxi/53/2002(H5N1)) linear GI:47156252 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 253. Influenza A virus 760 bp AY585390.1 (A/duck/Guangxi/53/2002(H5N1)) matrix linear GI:47156334 protein mRNA, complete cds mRNA 254. Influenza A virus 1,361 bp AY585412.1 (A/duck/Guangxi/53/2002(H5N1)) linear GI:47156378 neuraminidase (NA) mRNA, complete cds mRNA 255. Influenza A virus 1,498 bp AY585433.1 (A/duck/Guangxi/53/2002(H5N1)) linear GI:47156420 nucleoprotein (NP) mRNA, complete cds mRNA 256. Influenza A virus 687 bp AY585454.1 (A/duck/Guangxi/53/2002(H5N1)) linear GI:47156462 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 257. Influenza A virus 1,754 bp DQ449640.1 (A/duck/Kurgan/08/2005(H5N1)) linear GI:90289674 hemagglutinin (HA) mRNA, complete cds mRNA 258. Influenza A virus 1,002 bp DQ449641.1 (A/duck/Kurgan/08/2005(H5N1)) matrix linear GI:90289689 protein 1 (M) mRNA, complete cds mRNA 259. Influenza A virus 1,373 bp DQ449642.1 (A/duck/Kurgan/08/2005(H5N1)) linear GI:90289708 neuraminidase (NA) mRNA, complete cds mRNA 260. Influenza A virus 1,540 bp DQ449643.1 (A/duck/Kurgan/08/2005(H5N1)) linear GI:90289731 nucleoprotein (NP) mRNA, complete cds mRNA 261. Influenza A virus 850 bp DQ449644.1 (A/duck/Kurgan/08/2005(H5N1)) linear GI:90289739 nonstructural protein (NS) mRNA, mRNA complete cds 262. Influenza A virus 2,208 bp DQ449645.1 (A/duck/Kurgan/08/2005(H5N1)) linear GI:90289756 polymerase acidic protein (PA) mRNA, mRNA complete cds 263. Influenza A virus 2,316 bp DQ449646.1 (A/duck/Kurgan/08/2005(H5N1)) linear GI:90289774 polymerase basic protein 1 (PB1) mRNA mRNA, complete cds 264. Influenza A virus 2,316 bp DQ449647.1 (A/duck/Kurgan/08/2005(H5N1)) linear GI:90289783 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 266. Influenza A virus 2,281 bp AY585518.1 (A/duck/Shanghai/08/2001(H5N1)) linear GI:47156254 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 267. Influenza A virus 760 bp AY585391.1 (A/duck/Shanghai/08/2001(H5N1)) linear GI:47156336 matrix protein mRNA, complete cds mRNA 268. Influenza A virus 1,357 bp AY585413.1 (A/duck/Shanghai/08/2001(H5N1)) linear GI:47156380 neuraminidase (NA) mRNA, complete cds mRNA 269. Influenza A virus 1,498 bp AY585434.1 (A/duck/Shanghai/08/2001(H5N1)) linear GI:47156422 nucleoprotein (NP) mRNA, complete cds mRNA 270. Influenza A virus 685 bp AY585455.1 (A/duck/Shanghai/08/2001(H5N1)) linear GI:47156464 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 271. Influenza A virus 2,281 bp AY585519.1 (A/duck/Shanghai/13/2001(H5N1)) linear GI:47156256 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 272. Influenza A virus 760 bp AY585392.1 (A/duck/Shanghai/13/2001(H5N1)) linear GI:47156338 matrix protein mRNA, complete cds mRNA 273. Influenza A virus 1,417 bp AY585414.1 (A/duck/Shanghai/13/2001(H5N1)) linear GI:47156382 neuraminidase (NA) mRNA, complete cds mRNA 274. Influenza A virus 1,499 bp AY585435.1 (A/duck/Shanghai/13/2001(H5N1)) linear GI:47156424 nucleoprotein (NP) mRNA, complete cds mRNA 275. Influenza A virus 685 bp AY585456.1 (A/duck/Shanghai/13/2001(H5N1)) linear GI:47156466 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 276. Influenza A virus 2,281 bp AY585520.1 (A/duck/Shanghai/35/2002(H5N1)) linear GI:47156258 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 277. Influenza A virus 760 bp AY585393.1 (A/duck/Shanghai/35/2002(H5N1)) linear GI:47156340 matrix protein mRNA, complete cds mRNA 278. Influenza A virus 1,363 bp AY585415.1 (A/duck/Shanghai/35/2002(H5N1)) linear GI:47156384 neuraminidase (NA) mRNA, complete cds mRNA 279. Influenza A virus 1,498 bp AY585436.1 (A/duck/Shanghai/35/2002(H5N1)) linear GI:47156426 nucleoprotein (NP) mRNA, complete cds mRNA 280. Influenza A virus 685 bp AY585457.1 (A/duck/Shanghai/35/2002(H5N1)) linear GI:47156468 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 281. Influenza A virus 2,281 bp AY585521.1 (A/duck/Shanghai/37/2002(H5N1)) linear GI:47156260 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 282. Influenza A virus 760 bp AY585394.1 (A/duck/Shanghai/37/2002(H5N1)) linear GI:47156342 matrix protein mRNA, complete cds mRNA 283. Influenza A virus 1,361 bp AY585416.1 (A/duck/Shanghai/37/2002(H5N1)) linear GI:47156386 neuraminidase (NA) mRNA, complete cds mRNA 284. Influenza A virus 1,497 bp AY585437.1 (A/duck/Shanghai/37/2002(H5N1)) linear GI:47156428 nucleoprotein (NP) mRNA, complete cds mRNA 285. Influenza A virus 685 bp AY585458.1 (A/duck/Shanghai/37/2002(H5N1)) linear GI:47156470 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 286. Influenza A virus 2,282 bp AY585522.1 (A/duck/Shanghai/38/2001(H5N1)) linear GI:47156262 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 287. Influenza A virus 760 bp AY585395.1 (A/duck/Shanghai/38/2001(H5N1)) linear GI:47156344 matrix protein mRNA, complete cds mRNA 288. Influenza A virus 1,355 bp AY585417.1 (A/duck/Shanghai/38/2001(H5N1)) linear GI:47156388 neuraminidase (NA) mRNA, complete cds mRNA 289. Influenza A virus 1,499 bp AY585438.1 (A/duck/Shanghai/38/2001(H5N1)) linear GI:47156430 nucleoprotein (NP) mRNA, complete cds mRNA 290. Influenza A virus 692 bp AY585459.1 (A/duck/Shanghai/38/2001(H5N1)) linear GI:47156472 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 291. Influenza A virus 875 bp DQ354059.1 (A/duck/Sheyang/1/2005(H5N1)) linear GI:87128643 nonstructural protein (NS) mRNA, mRNA complete cds 292. Influenza A virus 1,748 bp DQ861291.1 (A/duck/Tuva/01/2006(H5N1)) linear GI:112820195 hemagglutinin (HA) mRNA, complete cds mRNA 293. Influenza A virus 991 bp DQ861292.1 (A/duck/Tuva/01/2006(H5N1)) matrix linear GI:112820197 protein 1 (M1) mRNA, complete cds mRNA 294. Influenza A virus 1,364 bp DQ861293.1 (A/duck/Tuva/01/2006(H5N1)) linear GI:112820199 neuraminidase (NA) mRNA, complete cds mRNA 295. Influenza A virus 1,531 bp DQ861294.1 (A/duck/Tuva/01/2006(H5N1)) linear GI:112820201 nucleoprotein (NP) mRNA, complete cds mRNA 296. Influenza A virus 842 bp DQ861295.1 (A/duck/Tuva/01/2006(H5N1)) linear GI:112820203 nonstructural protein (NS) mRNA, mRNA complete cds 297. Influenza A virus 890 bp DQ366310.1 (A/duck/Vietnam/1/2005(H5N1)) linear GI:86753715 nonstructural protein 1 mRNA, mRNA complete cds 298. Influenza A virus 2,341 bp DQ366303.1 (A/duck/Vietnam/1/2005(H5N1)) linear GI:86753725 polymerase PB2 mRNA, complete cds mRNA 299. Influenza A virus 2,341 bp DQ366304.1 (A/duck/Vietnam/1/2005(H5N1)) linear GI:86753735 polymerase PB1 mRNA, complete cds mRNA 300. Influenza A virus 2,233 bp DQ366305.1 (A/duck/Vietnam/1/2005(H5N1)) PA linear GI:86753745 protein mRNA, complete cds mRNA 301. Influenza A virus 1,779 bp DQ366306.1 (A/duck/Vietnam/1/2005(H5N1)) linear GI:86753755 hemagglutinin mRNA, complete cds mRNA 302. Influenza A virus 1,565 bp DQ366307.1 (A/duck/Vietnam/1/2005(H5N1)) linear GI:86753765 nucleocapsid mRNA, complete cds mRNA 303. Influenza A virus 1,401 bp DQ366308.1 (A/duck/Vietnam/1/2005(H5N1)) linear GI:86753775 neuraminidase mRNA, complete cds mRNA 304. Influenza A virus 1,027 bp DQ366309.1 (A/duck/Vietnam/1/2005(H5N1)) matrix linear GI:86753785 protein mRNA, complete cds mRNA 305. Influenza A virus 890 bp DQ366326.1 (A/duck/Vietnam/8/05(H5N1)) linear GI:86753719 nonstructural protein 1 mRNA, mRNA complete cds 306. Influenza A virus 2,341 bp DQ366319.1 (A/duck/Vietnam/8/05(H5N1)) linear GI:86753729 polymerase PB2 mRNA, complete cds mRNA 307. Influenza A virus 2,341 bp DQ366320.1 (A/duck/Vietnam/8/05(H5N1)) linear GI:86753739 polymerase PB1 mRNA, complete cds mRNA 308. Influenza A virus 2,233 bp DQ366321.1 (A/duck/Vietnam/8/05(H5N1)) PA linear GI:86753749 protein mRNA, complete cds mRNA 309. Influenza A virus 1,779 bp DQ366322.1 (A/duck/Vietnam/8/05(H5N1)) linear GI:86753759 hemagglutinin mRNA, complete cds mRNA 310. Influenza A virus 1,565 bp DQ366323.1 (A/duck/Vietnam/8/05(H5N1)) linear GI:86753769 nucleocapsid mRNA, complete cds mRNA 311. Influenza A virus 1,401 bp DQ366324.1 (A/duck/Vietnam/8/05(H5N1)) linear GI:86753779 neuraminidase mRNA, complete cds mRNA 312. Influenza A virus 1,027 bp DQ366325.1 (A/duck/Vietnam/8/05(H5N1)) matrix linear GI:86753789 protein mRNA, complete cds mRNA 313. Influenza A virus 876 bp DQ354060.1 (A/duck/Yangzhou/232/2004(H5N1)) linear GI:87128645 nonfunctional nonstructural protein mRNA (NS) mRNA, complete sequence 314. Influenza A virus 2,281 bp AY585523.1 (A/duck/Zhejiang/11/2000(H5N1)) linear GI:47156264 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 315. Influenza A virus 760 bp AY585396.1 (A/duck/Zhejiang/11/2000(H5N1)) linear GI:47156346 matrix protein mRNA, complete cds mRNA 316. Influenza A virus 1,352 bp AY585418.1 (A/duck/Zhejiang/11/2000(H5N1)) linear GI:47156390 neuraminidase (NA) mRNA, complete cds mRNA 317. Influenza A virus 1,498 bp AY585439.1 (A/duck/Zhejiang/11/2000(H5N1)) linear GI:47156432 nucleoprotein (NP) mRNA, complete cds mRNA 318. Influenza A virus 687 bp AY585460.1 (A/duck/Zhejiang/11/2000(H5N1)) linear GI:47156474 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 319. Influenza A virus 2,281 bp AY585524.1 (A/duck/Zhejiang/52/2000(H5N1)) linear GI:47156266 polymerase basic protein 2 (PB2) mRNA mRNA, complete cds 320. Influenza A virus 760 bp AY585397.1 (A/duck/Zhejiang/52/2000(H5N1)) linear GI:47156348 matrix protein mRNA, complete cds mRNA 321. Influenza A virus 1,423 bp AY585419.1 (A/duck/Zhejiang/52/2000(H5N1)) linear GI:47156392 neuraminidase (NA) mRNA, complete cds mRNA 322. Influenza A virus 1,499 bp AY585440.1 (A/duck/Zhejiang/52/2000(H5N1)) linear GI:47156434 nucleoprotein (NP) mRNA, complete cds mRNA 323. Influenza A virus 686 bp AY585461.1 (A/duck/Zhejiang/52/2000(H5N1)) linear GI:47156476 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 324. Influenza A virus (A/Egypt/0636- 1,749 bp EF382359.1 NAMRU3/2007(H5N1)) hemagglutinin (HA) linear GI:124244205 mRNA, complete cds mRNA 325. Influenza A virus 1,707 bp EF110518.1 (A/goosander/Switzerland/V82/06 linear GI:119394674 (H5N1)) hemagglutinin (HA) gene, mRNA complete cds 326. Influenza A virus 1,707 bp AF148678.1 (A/goose/Guangdong/1/96/(H5N1)) linear GI:5007022 hemagglutinin mRNA, complete cds mRNA 327. Influenza A virus 1,779 bp DQ201829.1 (A/Goose/Huadong/1/2000(H5N1)) linear GI:76786306 hemagglutinin (HA) mRNA, complete cds mRNA 328. Influenza A virus 1,458 bp DQ201830.1 (A/Goose/Huadong/1/2000(H5N1)) linear GI:76786308 neuraminidase (NA) mRNA, complete cds mRNA 329. Influenza A virus 2,287 bp EF446768.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428373 polymerase PB1 (PB1) mRNA, partial mRNA cds 330. Influenza A virus 2,274 bp EF446769.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428375 polymerase PB2 (PB2) mRNA, partial mRNA cds 331. Influenza A virus 2,175 bp EF446770.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428377 polymerase PA (PA) mRNA, complete cds mRNA 332. Influenza A virus 1,735 bp EF446771.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428379 hemagglutinin (HA) mRNA, complete cds mRNA 333. Influenza A virus 1,473 bp EF446772.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428381 nucleocapsid protein (NP) mRNA, mRNA partial cds 334. Influenza A virus 1,311 bp EF446773.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428383 neuraminidase (NA) mRNA, partial cds mRNA 335. Influenza A virus 971 bp EF446774.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428385 matrix protein 1 (M1) mRNA, partial mRNA cds 336. Influenza A virus 795 bp EF446775.1 (A/goose/Hungary/2823/2/2007(H5N1)) linear GI:126428387 nonstructural protein 1 (NS1) mRNA, mRNA partial cds 337. Influenza A virus 2,277 bp EF446776.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428389 polymerase PB1 (PB1) mRNA, partial mRNA cds 338. Influenza A virus 2,274 bp EF446777.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428391 polymerase PB2 (PB2) mRNA, partial mRNA cds 339. Influenza A virus 2,163 bp EF446778.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428393 polymerase PA (PA) mRNA, partial cds mRNA 340. Influenza A virus 1,722 bp EF446779.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428395 hemagglutinin (HA) mRNA, complete cds mRNA 341. Influenza A virus 1,463 bp EF446780.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428397 nucleocapsid protein (NP) mRNA, mRNA partial cds 342. Influenza A virus 1,289 bp EF446781.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428399 neuraminidase (NA) mRNA, partial cds mRNA 343. Influenza A virus 955 bp EF446782.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428401 matrix protein 1 (M1) mRNA, partial mRNA cds 344. Influenza A virus 805 bp EF446783.1 (A/goose/Hungary/3413/2007(H5N1)) linear GI:126428403 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 345. Influenza A virus 877 bp DQ354061.1 (A/goose/jiangsu/131/2002(H5N1)) linear GI:87128646 nonfunctional nonstructural protein mRNA (NS) mRNA, complete sequence 346. Influenza A virus 875 bp DQ354062.1 (A/goose/Jiangsu/220/2003(H5N1)) linear GI:87128647 nonstructural protein (NS) mRNA, mRNA complete cds 347. Influenza A virus 1,754 bp DQ676840.1 (A/goose/Krasnoozerka/627/2005(H5N1)) linear GI:108782531 hemagglutinin (HA) mRNA, complete cds mRNA 348. Influenza A virus 1,530 bp DQ676841.1 (A/goose/Krasnoozerka/627/2005(H5N1)) linear GI:108782533 nucleoprotein (NP) mRNA, complete cds mRNA 349. Influenza A virus 850 bp DQ676842.1 (A/goose/Krasnoozerka/627/2005(H5N1)) linear GI:108782535 nonstructural protein (NS) mRNA, mRNA complete cds 350. Influenza A virus 890 bp DQ366318.1 (A/goose/Vietnam/3/05(H5N1)) linear GI:86753717 nonstructural protein 1 mRNA, mRNA complete cds 351. Influenza A virus 2,341 bp DQ366311.1 (A/goose/Vietnam/3/05(H5N1)) linear GI:86753727 polymerase PB2 mRNA, complete cds mRNA 352. Influenza A virus 2,341 bp DQ366312.1 (A/goose/Vietnam/3/05(H5N1)) linear GI:86753737 polymerase PB1 mRNA, complete cds mRNA 353. Influenza A virus 2,233 bp DQ366313.1 (A/goose/Vietnam/3/05(H5N1)) PA linear GI:86753747 protein mRNA, complete cds mRNA 354. Influenza A virus 1,779 bp DQ366314.1 (A/goose/Vietnam/3/05(H5N1)) linear GI:86753757 hemagglutinin mRNA, complete cds mRNA 355. Influenza A virus 1,565 bp DQ366315.1 (A/goose/Vietnam/3/05(H5N1)) linear GI:86753767 nucleocapsid mRNA, complete cds mRNA 356. Influenza A virus 1,401 bp DQ366316.1 (A/goose/Vietnam/3/05(H5N1)) linear GI:86753777 neuraminidase mRNA, complete cds mRNA 357. Influenza A virus 1,027 bp DQ366317.1 (A/goose/Vietnam/3/05(H5N1)) matrix linear GI:86753787 protein mRNA, complete cds mRNA 358. Influenza A virus 1,700 bp AF082043.1 (A/gull/Pennsylvania/4175/83(H5N1)) linear GI:4240453 hemagglutinin H5 mRNA, partial cds mRNA 360. Influenza A virus 1,388 bp AF028708.1 (A/HongKong/156/97(H5N1)) linear GI:2865377 neuraminidase mRNA, complete cds mRNA 361. Influenza A virus 1,741 bp AF028709.1 (A/HongKong/156/97(H5N1)) linear GI:2865379 hemagglutinin mRNA, complete cds mRNA 362. Influenza A virus 1,549 bp AF028710.1 (A/HongKong/156/97(H5N1)) linear GI:2865381 nucleoprotein mRNA, complete cds mRNA 363. Influenza A virus (A/hooded 1,451 bp AM503028.1 vulture/Burkina Faso/1/2006(H5N1)) linear GI:147846292 partial mRNA for nucleoprotein (np mRNA gene) 364. Influenza A virus (A/hooded 827 bp AM503038.1 vulture/Burkina Faso/1/2006(H5N1)) linear GI:147846312 mRNA for non-structural protein (ns mRNA gene) 365. Influenza A virus (A/hooded 2,169 bp AM503047.1 vulture/Burkina Faso/1/2006(H5N1)) linear GI:147846330 partial mRNA for polymerase (pa gene) mRNA 366. Influenza A virus (A/hooded 1,686 bp AM503065.1 vulture/Burkina Faso/1/2006(H5N1)) linear GI:147846855 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 367. Influenza A virus (A/hooded 977 bp AM503006.1 vulture/Burkina Faso/2/2006(H5N1)) linear GI:147846248 partial mRNA for matrix protein 1 (m1 mRNA gene) 368. Influenza A virus (A/hooded 1,336 bp AM503017.1 vulture/Burkina Faso/2/2006(H5N1)) linear GI:147846270 partial mRNA for neuraminidase (na mRNA gene) 369. Influenza A virus (A/hooded 1,499 bp AM503027.1 vulture/Burkina Faso/2/2006(H5N1)) linear GI:147846290 partial mRNA for nucleoprotein (np mRNA gene) 370. Influenza A virus (A/hooded 827 bp AM503039.1 vulture/Burkina Faso/2/2006(H5N1)) linear GI:147846314 mRNA for non-structural protein (ns mRNA gene) 371. Influenza A virus (A/hooded 2,169 bp AM503048.1 vulture/Burkina Faso/2/2006(H5N1)) linear GI:147846332 partial mRNA for polymerase (pa gene) mRNA 372. Influenza A virus (A/hooded 2,259 bp AM503062.1 vulture/Burkina Faso/2/2006(H5N1)) linear GI:147846849 partial mRNA for polymerase basic mRNA protein 1 (pb1 gene) 373. Influenza A virus (A/hooded 2,315 bp AM503066.1 vulture/Burkina Faso/2/2006(H5N1)) linear GI:147846857 partial mRNA for polymerase basic mRNA protein 2 (pb2 gene) 374. Influenza A virus 294 bp EU014135.1 (A/Indonesia/CDC177/2005(H5N1)) M2 linear GI:151336850 protein mRNA, complete cds mRNA 375. Influenza A virus 294 bp EU014138.1 (A/Indonesia/CDC298/2005(H5N1)) M2 linear GI:151336856 protein mRNA, complete cds mRNA 376. Influenza A virus 294 bp EU014136.1 (A/Indonesia/CDC485/2006(H5N1)) M2 linear GI:151336852 protein mRNA, complete cds mRNA 377. Influenza A virus 294 bp EU014134.1 (A/Indonesia/CDC530/2006(H5N1)) M2 linear GI:151336848 protein mRNA, complete cds mRNA 378. Influenza A virus 294 bp EU014133.1 (A/Indonesia/CDC535/2006(H5N1)) M2 linear GI:151336846 protein mRNA, complete cds mRNA 379. Influenza A virus 294 bp EU014132.1 (A/Indonesia/CDC540/2006(H5N1)) M2 linear GI:151336844 protein mRNA, complete cds mRNA 380. Influenza A virus 294 bp EU014137.1 (A/Indonesia/CDC561/2006(H5N1)) M2 linear GI:151336854 protein mRNA, complete cds mRNA 381. Influenza A virus 294 bp EU014139.1 (A/Indonesia/CDC60/2005(H5N1)) M2 linear GI:151336858 protein mRNA, complete cds mRNA 382. Influenza A virus 996 bp U79453.1 (A/mallard/Wisconsin/428/75(H5N1)) linear GI:1840071 hemagglutinin mRNA, partial cds mRNA 383. Influenza A virus 441 bp JN157759.1 (A/ostrich/VRLCU/Egypt/2011(H5N1)) linear GI:338223304 segment 4 hemagglutinin (HA) mRNA, mRNA partial cds 384. Influenza A virus 875 bp DQ354063.1 (A/quail/yunnan/092/2002(H5N1)) linear GI:87128649 nonstructural protein (NS) mRNA, mRNA complete cds 385. Influenza A virus 1,472 bp AB241613.1 (A/R(Turkey/Ontario/7732/66- linear GI:82581222 Bellamy/42)(H5N1)) HA mRNA for mRNA hemagglutinin, partial cds 386. Influenza A virus 1,350 bp AY679513.1 (A/Thailand/LFPN-2004/2004(H5N1)) linear GI:50843945 neuraminidase mRNA, complete cds mRNA 387. Influenza A virus 1,704 bp AY679514.1 (A/Thailand/LFPN-2004/2004(H5N1)) linear GI:50843949 hemagglutinin mRNA, complete cds mRNA 388. Influenza A virus 534 bp DQ017251.1 (A/tiger/Thailand/CU-T4/04(H5N1)) linear GI:65329524 polymerase basic protein 2 (PB2) mRNA mRNA, partial cds 389. Influenza A virus 582 bp DQ017252.1 (A/tiger/Thailand/CU-T5/04(H5N1)) linear GI:65329536 polymerase basic protein 2 (PB2) mRNA mRNA, partial cds 390. Influenza A virus 564 bp DQ017253.1 (A/tiger/Thailand/CU-T6/04(H5N1)) linear GI:65329553 polymerase basic protein 2 (PB2) mRNA mRNA, partial cds 391. Influenza A virus 582 bp DQ017254.1 (A/tiger/Thailand/CU-T8/04(H5N1)) linear GI:65329568 polymerase basic protein 2 (PB2) mRNA mRNA, partial cds 392. Influenza A virus 1,695 bp EF441263.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307104 hemagglutinin (HA) mRNA, partial cds mRNA 393. Influenza A virus 943 bp EF441264.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307106 matrix protein (M) mRNA, partial cds mRNA 394. Influenza A virus 812 bp EF441265.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307109 nonstructural protein 1 (NS1) mRNA, mRNA complete cds 395. Influenza A virus 2,185 bp EF441266.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307111 polymerase PA (PA) mRNA, complete cds mRNA 396. Influenza A virus 2,272 bp EF441267.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307113 polymerase PB2 (PB2) mRNA, partial mRNA cds 397. Influenza A virus 1,396 bp EF441268.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307115 nucleocapsid (NP) mRNA, partial cds mRNA 398. Influenza A virus 2,288 bp EF441269.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307117 polymerase PB1 (PB1) mRNA, partial mRNA cds 399. Influenza A virus 1,276 bp EF441270.1 (A/turkey/England/250/2007(H5N1)) linear GI:129307119 neuraminidase (NA) mRNA, partial cds mRNA A/chicken/Burkina AM503016.1 Faso/13.1/2006(H5N1) neuraminidase (NA) A/chicken/Crimea/04/2005(H5N1) DQ650661.1 neuraminidase (NA) A/chicken/Crimea/04/2005(H5N1) DQ650659.1 hemagglutinin A/chicken/Crimea/08/2005(H5N1) DQ650669.1 polymerase basic protein 1 (PB1) A/chicken/Crimea/08/2005(H5N1) DQ650665.1 neuraminidase (NA) A/chicken/Crimea/08/2005(H5N1) DQ650663.1 hemagglutinin (HA) A/chicken/Guangxi/12/2004(H5N1) DQ366334.1 nonstructural protein 1 A/chicken/Guangxi/12/2004(H5N1) DQ366332.1 neuraminidase A/chicken/Guangxi/12/2004(H5N1) DQ366330.1 hemagglutinin A/duck/Kurgan/08/2005(H5N1) DQ449643.1 nucleoprotein (NP)

TABLE 9 Other Influenza A Antigens (H1N*, H2N*, H3N*) GenBank/GI Accession Strain/Protein Length Nos. H1N* Influenza A virus (A/duck/Hong 1,402 bp U49097.1 Kong/193/1977(H1N2)) nucleoprotein linear GI:1912392 (NP) mRNA, partial cds mRNA Influenza A virus (A/duck/Hong 258 bp U48285.1 Kong/193/1977(H1N2)) polymerase linear GI:1912374 (PB1) mRNA, partial cds mRNA Influenza A virus 795 bp AJ519455.1 (A/England/2/2002(H1N2)) partial NS1 linear GI:31096426 gene for non structural protein 1 and mRNA partial NS2 gene for non structural protein 2, genomic RNA Influenza A virus (A/England/3/ 384 bp AJ489497.1 02(H1N2)) partial mRNA for linear GI:27526856 nucleoprotein (np gene) mRNA Influenza A virus (A/England/3/ 442 bp AJ489488.1 02(H1N2)) partial mRNA for polymerase linear GI:27526838 subunit 2 (pb2 gene) mRNA Influenza A virus (A/England/5/ 384 bp AJ489498.1 02(H1N2)) partial mRNA for linear GI:27526858 nucleoprotein (np gene) mRNA Influenza A virus (A/England/5/ 442 bp AJ489489.1 02(H1N2)) partial mRNA for polymerase linear GI:27526840 subunit 2 (pb2 gene) mRNA Influenza A virus (A/England/57/ 384 bp AJ489499.1 02(H1N2)) partial mRNA for linear GI:27526860 nucleoprotein (np gene) mRNA Influenza A virus (A/England/57/ 442 bp AJ489492.1 02(H1N2)) partial mRNA for polymerase linear GI:27526846 subunit 2 (pb2 gene) mRNA Influenza A virus 384 bp AJ489496.1 (A/England/691/01(H1N2)) partial mRNA linear GI:27526854 for nucleoprotein (np gene) mRNA Influenza A virus (A/England/73/ 384 bp AJ489500.1 02(H1N2)) partial mRNA for linear GI:27526862 nucleoprotein (np gene) mRNA Influenza A virus (A/England/73/ 442 bp AJ489493.1 02(H1N2)) partial mRNA for polymerase linear GI:27526848 subunit 2 (pb2 gene) mRNA Influenza A virus (A/England/90/ 384 bp AJ489501.1 02(H1N2)) partial mRNA for linear GI:27526864 nucleoprotein (np gene) mRNA Influenza A virus (A/England/90/ 442 bp AJ489490.1 02(H1N2)) partial mRNA for polymerase linear GI:27526842 subunit 2 (pb2 gene) mRNA Influenza A virus (A/England/97/ 384 bp AJ489502.1 02(H1N2)) partial mRNA for linear GI:27526866 nucleoprotein (np gene) mRNA Influenza A virus (A/England/97/ 442 bp AJ489491.1 02(H1N2)) partial mRNA for polymerase linear GI:27526844 subunit 2 (pb2 gene) mRNA Influenza A virus 384 bp AJ489494.1 (A/England/627/01(H1N2)) partial mRNA linear GI:27526850 for nucleoprotein (np gene) mRNA Influenza A virus 442 bp AJ489485.1 (A/England/627/01(H1N2)) partial mRNA linear GI:27526832 for polymerase subunit 2 (pb2 gene) mRNA Influenza A virus 442 bp AJ489487.1 (A/England/691/01(H1N2)) partial mRNA linear GI:27526836 for polymerase subunit 2 (pb2 gene) mRNA Influenza A virus (A/Egypt/96/ 747 bp AJ519457.1 2002(H1N2)) partial NS1 gene for non linear GI:31096432 structural mRNA protein 1 and partial NS2 gene for non structural protein 2, genomic RNA Influenza A virus (A/Israe1/6/2002(H1N2)) 773 bp AJ519456.1 partial NS1 gene for non structural linear GI:31096429 protein 1 and partial NS2 gene for non mRNA structural protein 2, genomic RNA Influenza A virus (A/Saudi 772 bp AJ519453.1 Arabia/2231/2001(H1N2)) partial NS1 gene linear GI:31096420 for non structural protein 1 and partial mRNA N52 gene for non structural protein 2, genomic RNA Influenza A virus 384 bp AJ489495.1 (A/Scotland/122/01(H1N2)) partial mRNA linear GI:27526852 for nucleoprotein (np gene) mRNA Influenza A virus 442 bp AJ489486.1 (A/Scotland/122/01(H1N2)) partial mRNA linear GI:27526834 for polymerase subunit 2 (pb2 gene) mRNA Influenza A virus 832 bp AY861443.1 (A/swine/Bakum/1832/2000(H1N2)) linear GI:57791765 hemagglutinin (HA) mRNA, partial cds mRNA Influenza A virus 467 bp AY870645.1 (A/swine/Bakum/1832/2000(H1N2)) linear GI:58042754 neuraminidase mRNA, partial cds mRNA Influenza A virus (A/swine/Cotes 1,039 bp AM503547.1 d'Armor/0040/2007(H1N2)) segment 4 linear GI:225578611 partial mRNA mRNA Influenza A virus (A/swine/Cotes 1,136 bp AM490224.3 d'Armor/0136 17/2006(H1N2)) partial linear GI:222062921 mRNA mRNA for haemagglutinin precursor (HA1 gene) Influenza A virus 1,778 bp AF085417.1 (A/swine/England/72685/96(H1N2)) linear GI:3831770 haemagglutinin precursor, mRNA, mRNA complete cds Influenza A virus 1,778 bp AF085416.1 (A/swine/England/17394/96(H1N2)) linear GI:3831768 haemagglutinin precursor, mRNA, mRNA complete cds Influenza A virus 1,778 bp AF085415.1 (A/swine/England/690421/95(H1N2)) linear GI:3831766 haemagglutinin precursor, mRNA, mRNA complete cds Influenza A virus 1,778 bp AF085414.1 (A/swine/England/438207/94(H1N2)) linear GI:3831764 haemagglutinin precursor, mRNA, mRNA complete cds Influenza A virus 1,427 bp AY129157.1 (A/Swine/Korea/CY02/02(H1N2)) linear GI:24286064 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus 952 bp AY129158.1 (A/Swine/Korea/CY02/02(H1N2)) matrix linear GI:24286066 protein (M) mRNA, complete cds mRNA Influenza A virus 1,542 bp AY129159.1 (A/Swine/Korea/CY02/02(H1N2)) linear GI:24286069 nucleoprotein (NP) mRNA, complete cds mRNA Influenza A virus 842 bp AY129160.1 (A/Swine/Korea/CY02/02(H1N2)) linear GI:24286081 nonstructural protein (NS) mRNA, mRNA complete cds Influenza A virus 2,165 bp AY129161.1 (A/Swine/Korea/CY02/02(H1N2)) linear GI:24286087 polymerase acidic protein 2 (PA) mRNA, mRNA complete cds Influenza A virus 2,274 bp AY129162.1 (A/Swine/Korea/CY02/02(H1N2)) linear GI:24286096 polymerase subunit 1 (PB1) mRNA, mRNA complete cds Influenza A virus 2,334 bp AY129163.1 (A/Swine/Korea/CY02/02(H1N2)) linear GI:24286100 polymerase subunit 2 (PB2) mRNA, mRNA complete cds Influenza A virus 1,778 bp AF085413.1 (A/swine/Scotland/410440/94(H1N2)) linear GI:3831762 haemagglutinin precursor, mRNA, mRNA complete cds Influenza A virus (A/swine/Spain/80598- 291 bp EU305436.1 LP4/2007(H1N2)) matrix protein 2 (M2) linear GI:168830657 mRNA, partial cds mRNA Influenza A virus 975 bp AJ517813.1 (A/Switzerland/3100/2002(H1N2)) partial linear GI:38422519 HA gene for Haemagglutinin, genomic mRNA RNA Influenza A virus (A/duck/Hong 1,387 bp U49095.1 Kong/717/1979(H1N3)) nucleoprotein (NP) linear GI:1912388 mRNA, partial cds mRNA Influenza A virus (A/duck/Hong 265 bp U48281.1 Kong/717/1979(H1N3)) polymerase (PB1) linear GI:1912366 mRNA, partial cds mRNA Influenza A virus (A/herring gull/New 971 bp AY664422.1 Jersey/780/86 (H1N3)) nonfunctional linear GI:51011826 matrix protein mRNA, partial sequence mRNA Influenza A virus 997 bp AY664426.1 (A/mallard/Alberta/42/77(H1N6)) linear GI:51011830 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 1,020 bp U85985.1 (A/swine/England/191973/92(H1N7)) linear GI:1835733 matrix protein M1 mRNA, complete cds mRNA Influenza A virus 1,524 bp U85987.1 (A/swine/England/191973/92(H1N7)) linear GI:1835737 nucleoprotein mRNA, complete cds mRNA Influenza A virus 1,458 bp U85988.1 (A/swine/England/191973/92(H1N7)) linear GI:1835739 neuraminidase mRNA, complete cds mRNA Influenza A virus 1,698 bp U85986.1 (A/swine/England/191973/92(H1N7)) linear GI:1835735 haemagglutinin HA mRNA, partial cds mRNA H2N* Influenza A virus (A/ruddy 917 bp AY664465.1 turnstone/Delaware/81/93 (H2N1)) linear GI:51011869 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus (A/ruddy 968 bp AY664429.1 turnstone/Delaware/34/93 (H2N1)) linear GI:51011833 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 925 bp AY664466.1 (A/Shorebird/Delaware/122/97(H2N1)) linear GI:51011870 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 958 bp AY664454.1 (A/shorebird/Delaware/138/97 (H2N1)) linear GI:51011858 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 958 bp AY664457.1 (A/shorebird/Delaware/111/97 (H2N1)) linear GI:51011861 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 979 bp AY664442.1 (A/shorebird/Delaware/24/98 (H2N1)) linear GI:51011846 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza virus type 2,233 bp M81579.1 A/Leningrad/134/17/57 (H2N2) PA RNA, linear GI:324935 complete cds mRNA Influenza A virus (STRAIN A/ 2,151 bp AJ243994.1 MALLARD/NEW YORK/6750/78) partial linear GI:5918195 mRNA for PA protein mRNA Influenza A virus (A/X-7(F1)/(H2N2)) 1,467 bp M11205.1 neuraminidase mRNA, complete cds linear GI:323969 mRNA Influenza A virus 1,009 bp AY664425.1 (A/mallard/Alberta/77/77 (H2N3)) linear GI:51011829 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 968 bp AY664447.1 (A/mallard/Alberta/226/98(H2N3)) linear GI:51011851 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus (A/sanderling/New 846 bp AY664477.1 Jersey/766/86 (H2N7)) nonfunctional linear GI:51011881 matrix protein mRNA, partial sequence mRNA Influenza A virus (A/laughing gull/New 907 bp AY664471.1 Jersey/798/86 (H2N7)) nonfunctional linear GI:51011875 matrix protein mRNA, partial sequence mRNA Influenza A virus (A/herring 960 bp AY664440.1 gull/Delaware/471/1986(H2N7)) linear GI:51011844 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus (A/ruddy 1,011 bp AY664423.1 turnstone/Delaware/142/98 (H2N8)) linear GI:51011827 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 906 bp AY664473.1 (A/pintail/Alberta/293/77 (H2N9)) linear GI:51011877 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus (A/blue-winged 961 bp AY664449.1 teal/Alberta/16/97 (H2N9)) nonfunctional linear GI:51011853 matrix protein mRNA, partial sequence mRNA Influenza A virus (A/Laughing gull/New 952 bp AY664437.1 Jersey/75/85 (H2N9)) nonfunctional matrix linear GI:51011841 protein mRNA, partial sequence mRNA Influenza A virus 959 bp AY664450.1 (A/mallard/Alberta/205/98 (H2N9)) linear GI:51011854 nonfunctional matrix protein mRNA, mRNA partial sequence H3N* Influenza A virus (A/duck/Eastern 1,458 bp EU429755.1 China/267/2003(H3N1)) segment 6 linear GI:167859475 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,458 bp EU429754.1 China/253/2003(H3N1)) segment 6 linear GI:167859473 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,458 bp EU429753.1 China/252/2003(H3N1)) segment 6 linear GI:167859471 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,458 bp EU429752.1 China/243/2003(H3N1)) segment 6 linear GI:167859469 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,458 bp EU429734.1 China/262/2003(H3N1)) segment 6 linear GI:167859433 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,459 bp EU429733.1 China/233/2003(H3N1)) segment 6 linear GI:167859431 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,458 bp EU429723.1 China/213/2003(H3N1)) segment 6 linear GI:167859411 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,458 bp EU429719.1 China/341/2003(H3N1)) segment 6 linear GI:167859403 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,458 bp EU429718.1 China/01/2002(H3N1)) segment 6 linear GI:167859401 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus 1,013 bp AY664434.1 (A/mallard/Alberta/22/76 (H3N6)) linear GI:51011838 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 970 bp AY664443.1 (A/mallard/Alberta/199/99(H3N6)) linear GI:51011847 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 922 bp AY664461.1 (A/shorebird/Delaware/222/97 (H3N6)) linear GI:51011865 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus (A/Duck/Hokkaido/8/80 984 bp AF079570.1 (H3N8)) hemagglutinin precursor, mRNA, linear GI:3414978 partial cds mRNA Influenza A virus (A/Duck/Hokkaido/8/80 1,497 bp AF079571.1 (H3N8)) nucleoprotein mRNA, complete linear GI:3414980 cds mRNA Influenza A virus 1,461 bp EU429797.1 (A/duck/Ukraine/1/1963(H3N8)) segment linear GI:167859559 6 mRNA neuraminidase (NA) mRNA, complete cds Influenza A virus (A/duck/Eastern 1,460 bp EU429698.1 China/19/2004(H3N8)) segment 6 linear GI:167859361 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,460 bp EU429700.1 China/90/2004(H3N8)) segment 6 linear GI:167859365 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,460 bp EU429787.1 China/18/2005(H3N8)) segment 6 linear GI:167859539 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus (A/duck/Eastern 1,460 bp EU429788.1 China/119/2005(H3N8)) segment 6 linear GI:167859541 neuraminidase (NA) mRNA, complete cds mRNA Influenza A virus 1,061 bp AF197246.1 (A/equine/Argentina/1/96(H3N8)) linear GI:6651512 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 1,061 bp AF197245.1 (A/equine/Argentina/2/94(H3N8)) linear GI:6651510 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 1,061 bp AF197244.1 (A/equine/Argentina/1/95(H3N8)) linear GI:6651508 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus HA partial gene for 1,026 bp AJ223194.1 haemagglutinin, genomic RNA, strain linear GI:2780201 A/equine/Berlin/3/89(H3N8) mRNA Influenza A virus HA partial gene for 1,006 bp AJ223195.1 haemagglutinin, genomic RNA, strain linear GI:2780203 A/equine/Berlin/4/89(H3N8) mRNA Influenza A virus 1,061 bp AF197242.1 (A/equine/Florida/1/94(H3N8)) linear GI:6651504 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 695 bp AY328471.1 (A/equine/Grobois/1/98(H3N8)) linear GI:32966577 nonstructural protein NS1 mRNA, mRNA complete cds Influenza A virus (A/equi 473 bp AY919314.1 2/Gotland/01(H3N8)) hemagglutinin HA1 linear GI:60250543 subunit mRNA, partial cds mRNA Influenza A virus 1,763 bp U58195.1 (A/eq/Kentucky/81(H3N8)) hemagglutinin linear GI:1377873 mRNA, complete cds mRNA Influenza A virus 1,061 bp AF197247.1 (A/equine/Kentucky/9/95(H3N8)) linear GI:6651514 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 1,061 bp AF197248.1 (A/equine/Kentucky/1/96(H3N8)) linear GI:6651516 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 1,061 bp AF197249.1 (A/equine/Kentucky/1/97(H3N8)) linear GI:6651518 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 1,061 bp AF197241.1 (A/equine/Kentucky/1/98(H3N8)) linear GI:6651502 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 1,497 bp AY383753.1 (A/equine/Santiago/85(H3N8)) linear GI:37223511 nucleoprotein mRNA, complete cds mRNA Influenza A virus 1,698 bp AY383755.1 (A/equine/Santiago/85(H3N8)) linear GI:37223515 hemagglutinin mRNA, complete cds mRNA Influenza A virus 1,413 bp AY383754.1 (A/equine/Santiago/85(H3N8)) linear GI:37223513 neuraminidase mRNA, complete cds mRNA Influenza A virus 1,061 bp AF197243.1 (A/equine/Saskatoon/1/90(H3N8)) linear GI:6651506 hemagglutinin precursor (HA1) mRNA, mRNA partial cds Influenza A virus 1,010 bp AY664432.1 (A/mallard/Alberta/114/97 (H3N8)) linear GI:51011836 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 961 bp AY664489.1 (A/mallard/Alberta/167/98 (H3N8)) linear GI:51011893 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 970 bp AY664445.1 (A/pintail/Alberta/37/99(H3N8)) linear GI:51011849 nonfunctional matrix protein mRNA, mRNA partial sequence Influenza A virus 922 bp AY664455.1 (A/sanderling/Delaware/65/99 (H3N8)) linear GI:51011859 nonfunctional matrix protein mRNA, mRNA partial sequence

TABLE 10 Other Inﬂuenza A Antigens (H4N*-H13N*) GenBank Strain/Protein Access No. H4N* A/chicken/Singapore/ 1992(H4N1) M2 protein EU014144.1 A/mallard/Alberta/47/98(H4N1) nonfunctional matrix protein AY664488.1 A/duck/Hong Kong/412/1978(H4N2) polymerase (PB1) U48279.1 A/mallard/Alberta/300/77 (H4N3) nonfunctional matrix protein AY664480.1 A/Duck/Czechoslovakia/S6(H4N6) segment 4 hemagglutinin AF290436.1 A/duck/Eastern China/376/2004(H4N6) segment 6neuraminidase (NA) EU429792.1 A/duck/Eastern China/01/2007(H4N6) segment 6 neuraminidase (NA) EU429790.1 A/duck/Eastern China/216/2007(H4N6) segment 6 neuraminidase (NA) EU429789.1 A/duck/Eastern China/166/2004(H4N6) segment 6 neuraminidase (NA) EU429746.1 A/duck/Eastern China/02/2003(H4N6) segment 6 neuraminidase (NA) EU429713.1 A/duck/Eastern China/160/2002(H4N6) segment 6 neuraminidase (NA) EU429706.1 A/mallard/Alberta/111/99(H4N6) nonfunctional matrix protein AY664482.1 A/mallard/Alberta/213/99 (H4N6) nonfunctional matrix protein AY664460.1 A/mallard/Alberta/30/98 (H4N6) nonfunctional matrix protein AY664484.1 A/blue-winged teal/Alberta/96/76 (H4N8) nonfunctional matrix protein AY664420.1 H5N* A/chicken/Florida/25717/1993(H5N2) hemagglutinin U05332.1 A/chicken/Hidalgo/26654-1368/1994(H5N2) hemagglutinin (HA) U37172.1 A/chicken/Jalisco/14585-660/1994(H5N2) hemagglutinin (HA) U37181.1 A/chicken/Mexico/26654-1374/1994(H5N2) hemagglutinin (HA) U37173.1 A/chicken/Mexico/31381-3/1994(H5N2) hemagglutinin (HA) U37176.1 A/chicken/Mexico/31381-6/1994(H5N2) hemagglutinin (HA) U37175.1 A/chicken/Mexico/31381-4/1994(H5N2) hemagglutinin (HA) U37174.1 A/chicken/Mexico/31381-5/1994(H5N2) hemagglutinin (HA) U37169.1 A/chicken/Mexico/31381-8/1994(H5N2) hemagglutinin (HA) U37170.1 A/Chicken/Mexico/31381-Avilab/94(H5N2)hemagglutinin (HA) L46585.1 A/chicken/Mexico/31382-1/1994(H5N2)hemagglutinin (HA) U37168.1 A/chicken/Mexico/31381-2/1994(H5N2) hemagglutinin (HA) U37167.1 A/chicken/Mexico/31381-1/1994(H5N2) hemagglutinin (HA) U37166.1 A/chicken/Mexico/31381-7/1994(H5N2) hemagglutinin (HA) U37165.1 A/chicken/Pennsylvania/13609/1993(H5N2) hemagglutinin U05331.1 A/chicken/Pennsylvania/1/1983(H5N2) hemagglutinin esterase precursor M18001.1 A/chicken/Pennsylvania/1370/1983(H5N2) hemagglutinin esterase precursor M10243.1 A/Chicken/Puebla/8623-607/94(H5N2) hemagglutinin (HA) L46586.1 A/chicken/Puebla/14586-654/1994(H5N2) hemagglutinin (HA) U37180.1 A/chicken/Puebla/14585-622/1994(H5N2) hemagglutinin (HA) U37179.1 A/chicken/Puebla/8623-607/1994(H5N2)hemagglutinin (HA) U37178.1 A/chicken/Puebla/8624-604/1994(H5N2) hemagglutinin (HA) U37177.1 A/Chicken/Queretaro/14588-19/95(H5N2) hemagglutinin (HA) L46587.1 A/chicken/Queretaro/7653-20/95(H5N2) hemagglutinin (HA) U79448.1 A/chicken/Queretaro/26654-1373/1994(H5N2) hemagglutinin (HA) U37171.1 A/chicken/Queretaro/14588-19/1994(H5N2)hemagglutinin (HA) U37182.1 A/chicken/Singapore/98(H5N2) matrix protein 2 (M2) EF682127.1 A/chicken/Taiwan/1209/03(H5N2) hemagglutinin protein (HA) AY573917.1 A/chicken/Taiwan/1209/03(H5N2) neuraminidase AY573918.1 A/duck/Eastern China/64/2004(H5N2) segment 6 neuraminidase (NA) EU429791.1 A/duck/Eastern China/264/2002(H5N2) segment 6 neuraminidase (NA) EU429744.1 A/duck/Eastern China/01/2001(H5N2) segment 6 neuraminidase (NA) EU429728.1 A/duck/Eastern China/06/2000(H5N2) segment 6 neuraminidase (NA) EU429722.1 A/duck/Hong Kong/342/78(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107452.1 A/duck/Hong Kong/342/78(H5N2) hemagglutinin precursor U20475.1 A/duck/Michigan/80(H5N2) hemagglutinin 1 chain U20474.1 A/duck/Michigan/80(H5N2) hemagglutinin U79449.1 A/duck/MN/1564/81(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107467.1 A/duck/Mongolia/54/2001(H5N2) hemagglutinin (HA) AB241614.2 A/duck/Primorie/2621/01 (H5N2) hema g glutinin (HA) AJ621811.3 A/duck/Primorie/2621/01(H5N2)nucleoprotein (NP) AJ621812.1 A/duck/Primorie/2621/01(H5N2) nonstructural protein (NS) AJ621813.1 A/duck/Pennsylvania/84(H5N2) hemagglutinin 1chain U20473.1 A/duck/Potsdam/1402-6/86(H5N2) hemagglutinin H5 AF082042.1 A/emu/Texas/39442/93(H5N2) hemaglutinin U28920.1 A/emu/Texas/39442/93(H5N2) hemaglutinin U28919.1 A/mallard/Alberta/645/80(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107471.1 A/mallard/AR/1C/2001(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107463.1 A/mallard/NY/189/82(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107465.1 A/mallard/MN/25/80(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107473.1 A/mallard/MI/18/80(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107470.1 A/mallard/Ohio/345/88 (H5N2) hemagglutinin U79450.1 A/parrot/CA/6032/04(H5N2) polymerase basic protein 2 (PB2) DQ256390.1 A/parrot/CA/6032/04(H5N2) polymerase basic protein 1 (PB1) DQ256389.1 A/parrot/CA/6032/04(H5N2) matrix protein (M) DQ256384.2 A/parrot/CA/6032/04(H5N2) hemagglutinin (HA) DQ256383.1 A/parrot/CA/6032/04(H5N2) neuraminidase (NA) DQ256385.1 A/parrot/CA/6032/04(H5N2) polymerase basic protein 2 (PB2) DQ256390.1 A/parrot/CA/6032/04(H5N2) nucleoprotein (NP) DQ256386.1 A/parrot/CA/6032/04(H5N2)) polymerase (PA) DQ256388.1 A/ruddy turnstone/Delaware/244/91 (H5N2) nonfunctional matrix protein AY664474.1 A/ruddy turnstone/Delaware/244/91 (H5N2) U05330.1 A/turkey/Colorado/72(H5N2) hemagglutinin 1 chain (HA) U20472.1 A/turkey/England/N28/73 (H5N2) hemagglutinin AY500365.1 A/turkey/TX/14082/81(H5N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107464.1 A/turkey/MN/1704/82(H5N2)) matrix protein 1 (M) and matrix protein 2 (M) DQ107472.1 A/turkey/Minnesota/10734/95(H5N2)) hemagglutinin U79455.1 A/turkey/Minnesota/3689-1551/81(H5N2) hemagglutinin U79454.1 A/chicken/Singapore/1997(H5N3) M2 protein EU014141.1 A/duck/Hokkaido/299/04(H5N3) hemagglutinin (HA) AB241626.1 A/duck/Hokkaido/193/04(H5N3) hemagglutinin (HA) AB241625.1 A/duck/Hokkaido/101/04(H5N3) hemagglutinin (HA) AB241624.1 A/duck/Hokkaido/447/00(H5N3) hemagglutinin (HA) AB241620.1 A/duck/Hokkaido/69/00(H5N3) hemagglutinin (HA) AB241619.1 A/duck/Hong Kong/205/77(H5N3) hemagglutinin H5 AF082038.1 A/duck/Hong Kong/698/79(H5N3) hemagglutinin H5 AF082039.1 A/duck/Hong Kong/308/78(H5N3) matrix protein 1(M) and matrix protein 2 (M) DQ107457.1 A/duck/Hong Kong/825/80(H5N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107455.1 A/duck/Hong Kong/820/80(H5N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107453.1 A/duck/Hong Kong/205/77(H5N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107456.1 A/Duck/Ho Chi Minh/014/78(H5N3) segment 4 hemagglutinin AF290443.1 A/duck/Jiangxi/6151/2003(H5N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107451.1 A/duck/Malaysia/F119-3/97(H5N3) hemagglutinin AF303057.1 A/duck/Miyagi/54/76(H5N3)hemagglutinin (HA) AB241615.1 A/duck/Mongolia/596/01(H5N3) hemagglutinin HA) AB241622.1 A/duck/Mongolia/500/01(H5N3)hemagglutinin (HA) AB241621.1 A/duck/Primorie/2633/01(H5N3) matrix protein (M1) AJ621810.1 A/duck/Primorie/2633/01(H5N3)nucleoprotein (NP) AJ621808.1 A/duck/Primorie/2633/01(H5N3)hemagglutinin (HA) AJ621807.1 A/duck/Primorie/2633/01(H5N3)nucleoprotein (NP) AJ621809.1 A/goose/Hong Kong/23/78(H5N3) matrix protein 1(M) and matrix protein 2 (M) DQ107454.1 A/mallard/Wisconsin/169/75(H5N3) hemagglutinin U79452.1 A/swan/Hokkaido/51/96(H5N3)hemagglutinin (HA) AB241617.1 A/swan/Hokkaido/4/96(H5N3) hemagglutinin (HA) AB241616.1 A/turkey/CA/6878/79(H5N3) matrix protein 1(M) and matrix protein 2 (M) DQ107469.1 A/tern/South Africa/61(H5N3) hemagglutinin precursor (HA) U20460.1 A/gull/Delaware/5/2000(H5N4) matrix protein 1 (M) and matrix protein 2 (M) DQ107459.1 A/gull/Delaware/4/2000(H5N4) matrix protein 1 (M) and matrix protein 2 (M) DQ107458.1 A/shorebird/Delaware/109/2000(H5N4) matrix protein 1 (M) DQ107460.1 A/shorebird/Delaware/243/2000(H5N4) matrix protein 1 (M) and matrix protein 2 (M) DQ107462.1 A/shorebird/Delaware/230/2000(H5N4) matrix protein 1 (M) and matrix protein 2 (M) DQ107461.1 A/mallard/Wisconsin/34/75(H5N6) hemagglutinin U79451.1 A/duck/Potsdam/2216-4/1984(H5N6) hemagglutinin H5 AF082041.1 A/shorebird/Delaware/207/98 (H5N8) nonfunctional matrix protein AY664456.1 A/shorebird/Delaware/27/98 (H5N8) nonfunctional matrix protein AY664453.1 A/herring gull/Delaware/281/98 (H5N8) nonfunctional matrix protein AY664452.1 A/mallard/Ohio/556/1987(H5N9) hemagglutinin (HA) U67783.2 A/turkey/Wisconsin/68(H5N9) hemagglutinin U79456.1 H6N* A/blue-winged teal/Alberta/685/82(H6N1) matrix protein 1(M) and matrix protein DQ107448.1 2 (M) A/chicken/Taiwan/7-5/99(H6N1) nucleocapsid protein (NP) AF261750.1 A/chicken/Taiwan/7-5/99(H6N1) matrix protein AF262213.1 A/chicken/Taiwan/7-5/99(H6N1) nonstructural protein AF262212.1 A/chicken/Taiwan/7-5/99(H6N1) polymerase (PA) AF262211.1 A/chicken/Taiwan/7-5/99(H6N1) polymerase subunit PB1 AF262210.1 A/chicken/Taiwan/7-5/99(H6N1) nucleocapsid protein (NP) AF261750.1 A/chicken/Taiwan/ns2/99(H6N1) segment 4 hemagglutinin (HAI) AF310985.1 A/chicken/Taiwan/na3/98(H6N1) segment 4 hemagglutinin (HAI) AF310984.1 A/chicken/Taiwan/7-5/99(H6N1) segment 4 hemagglutinin (HA1) AF310983.1 A/duck/Hong Kong/D73/76(H6N1) matrix protein 1 (M) and matrix protein 2 (M) DQ107432.1 A/duck/Taiwan/9/23-3/2000(H6N1) matrix protein 1 (M) and matrix protein 2 (M) DQ107407.1 A/pheasant/Hong Kong/FY479/2000(H6N1) matrix protein 1 (M) and matrix DQ107409.1 protein 2 (M) A/pheasant/Hong Kong/55P44/2002(H6N1) matrix protein 1 (M) and matrix DQ107412.1 protein 2 (M) A/quail/Hong Kong/YU421/2002(H6N1) matrix protein 1 (M) and matrix protein 2 DQ107414.1 (M) A/avian/NY/17150-7/2000(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107423.1 A/chicken/CA/285/2003(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107429.1 A/chicken/CA/375TR/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107428.1 A/chicken/CA/203/2003(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107426.1 A/chicken/NY/101250-7/2001(H6N2) matrix protein 1(M) and matrix protein 2 (M) DQ107419.1 A/chicken/CA/625/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107418.1 A/Chicken/California/0139/2001(H6N2)nucleoprotein (NP) AF474070.1 A/Chicken/California/650/2000(H6N2) nucleoprotein (NP) AF474069.1 A/Chicken/California/9420/2001(H6N2) neuraminidase N2 (N2) AF474048.1 A/Chicken/California/9174/2001(H6N2) neuraminidase N2 (N2) AF474047.1 A/Chicken/California/8892/2001(H6N2)neuraminidase N2 (N2) AF474046.1 A/Chicken/California/6643/2001(H6N2) neuraminidase N2 (N2) AF474045.1 A/Chicken/California/1316/2001(H6N2)neuraminidase N2 (N2) AF474044.1 A/Chicken/California/0139/2001(H6N2) neuraminidase N2 (N2) AF474043.1 A/Chicken/California/1002/2000(H6N2) neuraminidase N2 (N2) AF474042.1 A/Chicken/California/650/2000(H6N2) neuraminidase N2 (N2) AF474041.1 A/Chicken/California/465/2000(H6N2) neuraminidase N2 (N2) AF474040.1 A/Chicken/California/431/2000(H6N2) neuraminidase N2 (N2) AF474039.1 A/Chicken/California/6643/2001(H6N2) hemagglutinin H6 (H6) AF474035.1 A/Chicken/California/431/2000(H6N2) hemagglutinin H6 (H6) AF474029.1 A/Chicken/California/9420/2001(H6N2) hemagglutinin H6 (H6) AF474038.1 A/Chicken/California/9174/2001(H6N2) hemagglutinin H6 (H6) AF474037.1 A/Chicken/California/8892/2001(H6N2) hemagglutinin H6 (H6) AF474036.1 A/Chicken/California/1316/2001(H6N2) hemagglutinin H6 (H6) AF474034.1 A/Chicken/California/0139/2001(H6N2) hemagglutinin H6 (H6) AF474033.1 A/Chicken/California/1002/2000(H6N2) hemagglutinin H6 (H6) AF474032.1 A/Chicken/California/650/2000(H6N2) hemagglutinin H6 (H6) AF474031.1 A/Chicken/California/465/2000(H6N2) hemagglutinin H6 (H6) AF474030.1 A/cornish cross/CA/139/2001(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107424.1 A/duck/Eastern China/164/2002(H6N2) segment 6 neuraminidase (NA) EU429762.1 A/duck/Eastern China/729/2003(H6N2) segment 6 neuraminidase (NA) EU429760.1 A/duck/Eastern China/262/2002(H6N2) segment 6 neuraminidase (NA) EU429743.1 A/duck/Eastern China/74/2006(H6N2) segment 6 neuraminidase (NA) EU429741.1 A/duck/Eastern China/161/2002(H6N2) segment 6 neuraminidase (NA) EU429740.1 A/duck/Hong Kong/960/80(H6N2)) matrix protein 1 (M) and matrix protein 2 (M) DQ107435.1 A/duck/Hong Kong/D134/77(H6N2)) matrix protein 1 (M) and matrix protein 2 (M) DQ107433.1 A/duck/CA/10221/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107421.1 A/duck/Shantou/5540/2001(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107431.1 A/guinea fowl/Hong Kong/SSP99/2002(H6N2) matrix protein 1 (M) and matrix DQ107413.1 protein 2 (M) A/mallard/NY/016/83(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107449.1 A/mallard/NY/046/83(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107450.1 A/pintail/Alberta/644/81(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107445.1 A/quail/Hong Kong/SF792/2000(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107410.1 A/ruddy turnstone/Delaware/106/98 (H6N2) nonfunctional matrix protein AY664439.1 A/Shorebird/Delaware/127/97(H6N2) nonfunctional matrix protein AY664467.1 A/shorebird/Delaware/124/2001(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107417.1 A/shorebird/Delaware/208/2001(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107427.1 A/turkey/CA/527/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107420.1 A/turkey/CA/1623CT/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107425.1 A/turkey/MN/836/80(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107440.1 A/turkey/MN/735/79(H6N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107437.1 A/chicken/Hong Kong/17/77(H6N4)) matrix protein 1 (M) and matrix protein 2 (M) DQ107436.1 A/chicken/Hong Kong/CSW106/2001(H6N4) matrix protein 1 (M) and matrix DQ107406.1 protein 2 (M) A/gull/Delaware/18/2000(H6N4) matrix protein 1 (M) and matrix protein 2 (M) DQ107415.1 A/pheasant/Hong Kong/CSW2573/2001(H6N4) matrix protein 1 (M) and matrix DQ107411.1 protein 2 (M) A/quail/Hong Kong/CSW106/2001(H6N4) matrix protein 1 (M) and matrix protein DQ107430.1 2 (M) A/Shorebird/Delaware/194/98(H6N4) nonfunctional matrix protein AY664424.1 A/shorebird/Delaware/259/2000(H6N4) matrix protein 1 (M) and matrix protein 2 (M) DQ107416.1 A/shearwater/Australia/1/1972(H6N5) segment 6 neuraminidase (NA) EU429794.1 A/shearwater/Australia/1/1972(H6N5) polymerase A (PA) L25832.1 A/pintail/Alberta/1040/79(H6N5) matrix protein 1 (M) and matrix protein 2 (M) DQ107439.1 A/blue-winged teal/MN/993/80(H6N6)) matrix protein 1 (M) and matrix protein 2 (M) DQ107441.1 A/duck/NY/83779/2002(H6N6) matrix protein 1 (M) and matrix protein 2 (M) DQ107422.1 A/duck/MN/1414/81(H6N6) matrix protein 1 (M) and matrix protein 2 (M) DQ107444.1 A/mallard/Alberta/289/82(H6N6) matrix protein 1 (M) and matrix protein 2 (M) DQ107447.1 A/mallard duck/MN/1041/80(H6N6) matrix protein 1 (M) and matrix protein 2 (M) DQ107442.1 A/pintail/Alberta/189/82(H6N6) matrix protein 1 (M) and matrix protein 2 (M) DQ107446.1 A/sanderling/Delaware/1258/86(H6N6) nonfunctional matrix protein AY664436.1 A/blue-winged teal/Alberta/368/78(H6N8)) matrix protein 1 (M) and matrix protein 2 (M) DQ107438.1 A/ruddy turnstone/Delaware/105/98 (H6N8) nonfunctional matrix protein AY664428.1 A/domestic duck/NY/81(H6N8)) matrix protein (M) DQ107443.1 A/duck/Eastern China/163/2002(H6N8) segment 6 neuraminidase (NA) EU429786.1 A/duck/Hong Kong/D182/77(H6N9) matrix protein 1 (M) and matrix protein 2 (M) DQ107434.1 A/chicken/Hong Kong/SF3/2001(H6) matrix protein 1 (M) and matrix protein 2 (M) DQ107408.1 H7N* A/African starling/England/983/79(H7N1) neuraminidase (N1) AJ416629.1 A/Afri.Star./Eng-Q/938/79(H7N1) hemagglutinin precurosr AF149295.1 A/chicken/Italy/1067/99(H7N1) matrix protein 1 (M1) AJ416630.1 A/chicken/Italy/1067/99(H7N1) neuraminidase (N1) AJ416627.1 A/chicken/Italy/4575/99 (H7N1) hemagglutinin (HA) AJ493469.1 A/chicken/Italy/13474/99(H7N1) haemagglutinin (HA) AJ491720.1 A/chicken/Italy/445/1999(H7N1) AX537385.1 A/Chicken/Italy/267/00(H7N1) hemagglutinin (HA) AJ493215.1 A/Chicken/Italy/13489/99(H7N1) hemagglutinin (HA) AJ493214.1 A/Chicken/Italy/13307/99(H7N1) hemagglutinin (HA) AJ493212.1 A/chicken/Singapore/1994(H7N1) M2 protein EU014140.1 A/duck/Hong Kong/301/78(H7N1) matrix protein 1 (M) and matrix protein 2 (M) DQ107475.1 A/Hong Kong/301/78(H7N1) hemagglutinin (HA) AY672090.1 A/fowl plaguq virus/Rostock/34 (H7N1) NP protein AJ243993.1 A/fowl plaguq virus/Rostock/34 (H7N1) PA protein AJ243992.1 A/fowl plaguq virus/Rostock/34 (H7N1) PB2 protein AJ243991.1 A/fowl plaguq virus/Rostock/34 (H7N1) PB1 protein AJ243990.1 A/ostrich/South Africa/5352/92(H7N1) hemagglutinin precursor (HA) U20458.1 A/rhea/North Carolina/39482/93(H7N1) hemagglutinin precursor (HA) U20468.1 A/turkey/Italy/3775/99 (H7N1) hemagglutinin (HA) AJ493472.1 A/turkey/Italy/4603/99 (H7N1) hemagglutinin (HA) AJ493471.1 A/turkey/Italy/4602/99 (H7N1) hemagglutinin (HA) AJ493470.1 A/turkey/Italy/4169/99 (H7N1) hemagglutinin (HA) AJ493468.1 A/turkey/Italy/4073/99 (H7N1) hemagglutinin (HA) AJ493467.1 A/turkey/Italy/3889/99 (H7N1) hemagglutinin (HA) AJ493466.1 A/turkey/Italy/12598/99(H7N1) haemagglutinin (HA) AJ489520.1 A/turkey/Italy/4580/99(H7N1) haemagglutinin (HA) AJ416628.1 A/Turkey/Italy/335/00(H7N1) haemagglutinin (HA) AJ493217.1 A/Turkey/Italy/13468/99(H7N1) haemagglutinin (HA) AJ493216.1 A/Turkey/Italy/13467/99(H7N1) haemagglutinin (HA) AJ493213.1 A/chicken/CT/9407/2003(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107478.1 A/chicken/NY/116124/2003(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107479.1 A/chicken/PA/143586/2002(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107477.1 A/duck/Hong Kong/293/78(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107474.1 A/duck/Hong Kong/293/78(H7N2) hemagglutinin precursor (HA) U20461.1 A/laughing gull/Delaware/2838/87 (H7N2) nonfunctional matrix protein AY664427.1 A/pheasant/NJ/30739-9/2000(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107481.1 A/ruddy turnstone/Delaware/130/99 (H7N2) onfunctional matrix protein AY664451.1 A/unknown/149717-12/2002(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107480.1 A/unknown/NY/74211-5/2001(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107476.1 A/unknown/149717-12/2002(H7N2) matrix protein 1 (M) and matrix protein 2(M) DQ107480.1 A/unknown/NY/74211-5/2001(H7N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107476.1 A/chicken/British Columbia/CN7-3/04 (H7N3) hemagglutinin (HA) AY644402.1 A/chicken/British Columbia/CN7-3/04 (H7N3) matrix protein (M1) AY677732.1 A/chicken/Italy/270638/02(H7N3) hemagglutinin (HA) EU158111.1 A/gadwall/MD/3495/83(H7N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107488.1 A/mallard/Alberta/22/2001(H7N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107482.1 A/mallard/Alberta/699/81(H7N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107487.1 A/pintail/Alberta/25/2001(H7N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107483.1 A/Quail/Arkansas/16309-7/94 (H7N3) hemagglutinin protein subunit 1 precursor AF072401.1 (HA1) A/ruddy turnstone/New Jersey/65/85(H7N3) nonfunctional matrix protein AY664433.1 A/turkey/England/63(H7N3) hemagglutinin precursor (HA) U20462.1 A/Turkey/Colorado/13356/91 (H7N3) hemagglutinin protein subunit 1 precursor AF072400.1 (HA1) A/turkey/MN/1200/80(H7N3)) matrix protein 1 (M) and matrix protein 2 (M) DQ107486.1 A/turkey/MN/1818/82(H7N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107489.1 A/turkey/Minnesota/1237/80(H7N3) hemagglutinin precursor (HA) U20466.1 A/turkey/TX/1/79(H7N3) matrix protein 1 (M) and matrix protein 2 (M) DQ107484.1 A/Turkey/Oregon/71(H7N3) hemagglutinin AF497557.1 A/Turkey/Utah/24721-10/95 (H7N3) hemagglutinin protein subunit 1 precursor AF072402.1 (HA1) A/softbill/South Africa/142/92(H7N4) hemagglutinin precursor (HA) U20464.1 A/ruddy turnstone/Delaware/2770/87 (H7N5) nonfunctional matrix protein AY664476.1 A/chicken/Brescia/1902(H7N7) hemagglutinin 1 chain (HA) U20471.1 A/chicken/Jena/1816/87(H7N7) hemagglutinin precursor (HA) U20469.1 A/chicken/Leipzig/79(H7N7) hemagglutinin precursor (HA) U20459.1 A/duck/Heinersdorf/S495/6/86(H7N7) hemagglutinin precursor (HA) U20465.1 A/equine/Prague/1/56 (H7N7) neuraminidase U85989.1 A/equine/Santiago/77(H7N7) nucleoprotein AY383752.1 A/equine/Santiago/77(H7N7) neuraminidase AY383757.1 A/equine/Santiago/77(H7N7) hemagglutinin AY383756.1 A/FPV/Weybridge(H7N7) matrix protein M38299.1 A/goose/Leipzig/187/7/1979(H7N7) hemagglutinin L43914.1 A/goose/Leipzig/192/7/1979(H7N7) hemagglutinin L43915.1 A/goose/Leipzig/137/8/1979(H7N7) hemagglutinin L43913.1 A/ruddy turnstone/Delaware/134/99 (H7N7) nonfunctional matrix protein AY664468.1 A/seal/Mass/1/80 H7N7 recombinant S73497.1 A/swan/Potsdam/63/6/81(H7N7) hemagglutinin precursor (HA) U20467.1 A/tern/Potsdam/342/6/79(H7N7) hemagglutinin precursor (HA) U20470.1 A/pintail/Alberta/121/79(H7N8) matrix protein 1(M) and matrix protein 2 (M) DQ107485.1 A/Turkey/Minnesota/38429/88(H7N9) hemagglutinin AF497551.1 H8N* A/turkey/Ontario/6118/1968(H8N4) segment 6 neuraminidase (NA) EU429793.1 A/Mallard Duck/Alberta/357/84(H8N4) segment 4 hemagglutinin (HA1) AF310988.1 A/Pintail Duck/Alberta/114/79(H8N4) segment 4 hemagglutinin (HA1) AF310987.1 A/duck/Eastern China/01/2005(H8N4) segment 6 neuraminidase (NA) EU429780.1 A/Red Kont/Delaware/254/94(H8N4) segment 4 hemagglutinin (HA1) AF310989.1 H9N* A/chicken/Amioz/1527/03(H9N2) nucleoprotein DQ116511.1 A/chicken/Amioz/1527/03(H9N2) neuraminidase DQ116081.1 A/chicken/Amioz/1527/03(H9N2) hemagglutinin DQ108911.1 A/chicken/Alonim/1953/104(H9N2) hemagglutinin DQ108928.1 A/chicken/Alonim/1552/03(H9N2) hemagglutinin DQ108914.1 A/chicken/Alonim/1552/03(H9N2) nucleoprotein DQ116514.1 A/chicken/Alonim/1965/04(H9N2) hemagglutinin DQ108929.1 A/Chicken/Anhui/1/98(H9N2) hemagglutinin (HA) AF461511.1 A/Chicken/Beijing/1/95(H9N2) nonfunctional matrix protein AF536719.1 A/Chicken/Beijing/1/95(H9N2) nucleoprotein (NP) AF536699.1 A/Chicken/Beijing/1/95(H9N2) nonfunctional nonstructural protein AF536729.1 A/Chicken/Beijing/1/95(H9N2) segment 6 neuraminidase (NA) AF536709.1 A/Chicken/Beijing/2/97(H9N2) nucleoprotein (NP) AF536700.1 A/Chicken/Beijing/2/97(H9N2) nonfunctional matrix protein AF536720.1 A/Chicken/Beijing/2/97(H9N2) nonfunctional nonstructural protein AF536730.1 A/Chicken/Beijing/2/97(H9N2) segment 6 neuraminidase (NA) AF536710.1 A/Chicken/Beijing/1/97(H9N2) hemagglutinin (HA) AF461530.1 A/Chicken/Beijing/3/99(H9N2) nonfunctional matrix protein AF536721.1 A/Chicken/Beijing/3/99(H9N2) nucleoprotein (NP) AF536701.1 A/Chicken/Beijing/3/99(H9N2) nonfunctional nonstructural protein AF536731.1 A/Chicken/Beijing/3/99(H9N2) segment 6 neuraminidase (NA) AF536711.1 A/chicken/Beit Alfa/1282/03(H9N2)hemagglutinin DQ104476.1 A/chicken/Beit-Aran/29/05(H9N2) hemagglutinin DQ108931.1 A/chicken/Bnei Darom/1557/03(H9N2) hemagglutinin DQ108915.1 A/chicken/Ein Habsor/1808/04(H9N2) hemagglutinin DQ108925.1 A/Chicken/Gangxi/2/00(H9N2) hemagglutinin (HA) AF461514.1 A/Chicken/Gangxi/1/00(H9N2) hemagglutinin (HA) AF461513.1 A/chicken/Gan Shomron/1465/03(H9N2) hemagglutinin DQ104480.1 A/chicken/Gan Shomron/1292/03(H9N2) hemagglutinin DQ104478.1 A/chicken/Gan_Shomron/1465/03(H9N2) nucleoprotein DQ116506.1 A/chicken/Gan_Shomron/1465/03(H9N2) neuraminidase DQ116077.1 A/chicken/Gan Shomron/1543/04(H9N2) nucleoprotein DQ116512.1 A/chicken/Gan Shomron/1543/04(H9N2) hemagglutinin DQ108912.1 A/Chicken/Guangdong/97(H9N2) nonfunctional matrix protein AF536722.1 A/Chicken/Guangdong/97(H9N2) nucleoprotein (NP) AF536702.1 A/Chicken/Guangdong/97(H9N2) nonfunctional nonstructural protein AF536732.1 A/Chicken/Guangdong/97(H9N2) segment 6 neuraminidase (NA) AF536712.1 A/Chicken/Gansu/1/99(H9N2) hemagglutinin (HA) AF461512.1 A/chicken/Gujrat/India/3697/2004(H9N2) polymerase basic 2 (PB2) DQ979865.1 A/chicken/Haryana/India/2424/2004(H9N2) polymerase basic 2 (PB2) DQ979862.1 A/Chicken/Henan/98(H9N2) nonfunctional matrix protein AFS36726.1 A/Chicken/Henan/98(H9N2) nucleoprotein (NP) AFS36706.1 A/Chicken/Henan/98(H9N2) nonfunctional nonstructural protein AF536736.1 A/Chicken/Henan/2/98(H9N2) hemagglutinin (HA) AF461517.1 A/Chicken/Henan/1/99(H9N2) hemagglutinin (HA) AF461516.1 A/Chicken/Henan/98(H9N2) segment 6 neuraminidase (NA) AF536716.1 A/Chicken/Hebei/1/96(H9N2) nonfunctional matrix protein AF536723.1 A/Chicken/Hebei/1/96(H9N2) segment 6 nonfunctional neuraminidase protein AF536713.1 A/Chicken/Hebei/1/96(H9N2) nucleoprotein (NP) AF536703.1 A/Chicken/Hebei/1/96(H9N2) nonfunctional nonstructural protein AF536733.1 A/Chicken/Hebei/1/96(H9N2) segment 6 nonfunctional neuraminidase protein AF536713.1 A/Chicken/Hebei/2/00(H9N2) hemagglutinin (HA) AF461531.1 A/Chicken/Hebei/2/98(H9N2) nonfunctional matrix protein AF536724.1 A/Chicken/Hebei/2/98(H9N2) nucleoprotein (NP) AF536704.1 A/Chicken/Hebei/2/98(H9N2) nonfunctional nonstructural protein AF536734.1 A/Chicken/Hebei/2/98(H9N2) segment 6 neuraminidase (NA) AF536714.1 A/Chicken/Hebei/1/00(H9N2) hemagglutinin (HA) AF461515.1 A/Chicken/Hebei/3/98(H9N2) nucleoprotein (NP) AFS36705.1 A/Chicken/Hebei/3/98(H9N2) nonfunctional matrix protein AF536725.1 A/Chicken/Hebei/3/98(H9N2) nonfunctional onstructural protein AF536735.1 A/Chicken/Hebei/3/98(H9N)) segment 6 neuraminidase (NA) AFS36715.1 A/chicken/Hong Kong/FY313/2000(H9N2) matrix protein 1 (M) and matrix DQ107508.1 protein 2 (M) A/chicken/Hong Kong/WF208/2001(H9N2) matrix protein 1 (M) and matrix DQ107513.1 protein 2 (M) A/chicken/Hong Kong/NT471/2002(H9N2) matrix protein 1 (M) and matrix DQ107514.1 protein 2 (M) A/chicken/Hong Kong/WF2/99(H9N2) hemagglutinin AY206677.1 A/chicken/Iarah/1376/03(H9N2) nucleoprotein DQ116504.1 A/chicken/Iarah/1376/03(H9N2) neuraminidase DQ116075.1 A/chicken/Iarah/1376/03(H9N2) hemagglutinin DQ108910.1 A/chicken/India/2793/2003(H9N2) hemagglutinin (HA) AY336597.1 A/chicken/Iran/101/1998(H9N2) matrix protein 2 (M2) EU477375.1 A/Chicken/Jiangsu/1/99(H9N)) hemagglutinin (HA) AF461509.1 A/Chicken/Jiangsu/2/98(H9N2) hemagglutinin (HA) AF461510.1 A/chicken/Kfar Monash/636/02(H9N2) hemagglutinin DQ104464.1 A/chicken/Kalanit/1966/06.12.04(H9N2) hemagglutinin DQ108930.1 A/chicken/Kalanit/1946/04(H9N2) hemagglutinin DQ108927.1 A/chicken/Korea/S4/2003(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107517.1 A/Chicken/Korea/MS96/96(H9N2) matrix protein 1 and 2 (M) AF203788.1 A/Chicken/Korea/MS96/96(H9N2) neuraminidase subtype 2 AF203786.1 A/Chicken/Korea/MS96/96(H9N2) nucleoprotein AF203787.1 A/Chicken/Liaoning/99(H9N2) nonfunctional matrix protein AFS36727.1 A/Chicken/Liaoning/1/00(H9N2) hemagglutinin (HA) AF461518.1 A/Chicken/Liaoning/99(H9N2) nucleoprotein (NP) AFS36707.1 A/Chicken/Liaoning/99(H9N2) nonfunctional matrix protein AFS36727.1 A/Chicken/Liaoning/99(H9N2) nonfunctional onstructural protein AF536737.1 A/Chicken/Liaoning/2/00(H9N2) hemagglutinin (HA) AF461519.1 A/chicken/Liaoning/99(H9N2) segment 6 neuraminidase (NA) AF536717.1 A/chicken/Mudanjiang/0823/2000(H9N2) nucleoprotein (NP) AY496851.1 A/Chicken/Mudanjiang/0823/2000(H9N2) nonstructural protein AY631868.1 A/Chicken/Mudanjiang/0823/00(H9N2) hemagglutinin (HA) AY513715.1 A/chicken/Mudanjiang/0823/2000(H9N2) matrix protein (M1) AY496852.1 A/chicken/Mudanjiang/0823/2000(H9N2) nucleoprotein (np) AY496851.1 A/chicken/Maale HaHamisha/90658/00(H9N2) hemagglutinin DQ104472.1 A/chicken/Maanit/1477/03(H9N2) hemagglutinin DQ104483.1 A/chicken/Maanit/1291/03(H9N2) hemagglutinin DQ104477.1 A/chicken/Maanit/1275/03(H9N2) hemagglutinin DQ104457.1 A/chicken/Maanit/1477/03(H9N2) nucleoprotein DQ116508.1 A/chicken/Netohab/1373/03 (H9N2) nucleoprotein DQ116503.1 A/chicken/Netohab/1373/03 (H9N2) neuraminidase DQ116074.1 A/chicken/Netohab/1373/03 (H9N2) hemagglutinin DQ108909.1 A/chicken/Neve Ilan/1504/03(H9N2) hemagglutinin DQ104484.1 A/chicken/Neve_Ilan/1504/03(H9N2) nucleoprotein DQ116509.1 A/chicken/Neve_Ilan/1504/03(H9N2) neuraminidase DQ116079.1 A/chicken/Orissa/India/2317/2004(H9N2) polymerase basic 2 (PB2) DQ979861.1 A/chicken/Pardes-Hana-Carcur/1475/03(H9N2) hemagglutinin DQ104482.1 A/chicken/Pardes-Hana-Carcur/1475/03(H9N2) neuraminidase DQ116078.1 A/chicken/Saar/1456/03(H9N2) hemagglutinin DQ104479.1 A/chicken/Sde_Uziahu/1747/04(H9N2) neuraminidase DQ116068.1 A/chicken/Sede Uzziyyahu/1651/04(H9N2) hemagglutinin DQ108923.1 A/chicken/Sde Uziahu/1747/04(H9N2) DQ108905.1 A/chicken/Singapore/1998(H9N2) M2 protein EU014142.1 A/chicken/Singapore/1998(H9N2) M2 protein EU014142.1 A/Chicken/Shandong/98(H9N2) nonfunctional matrix protein AFS36728.1 A/Chicken/Shandong/1/98(H9N2) hemagglutinin (HA) AF461520.1 A/Chicken/Shandong/98(H9N2) nucleoprotein (NP) AFS36708.1 A/Chicken/Shandong/98(H9N2) nonfunctional nonstructural protein AF536738.1 A/Chicken/Shandong/98(H9N2) segment 6 neuraminidase (NA) AF536718.1 A/Chicken/Shandong/2/99(H9N2) hemagglutinin (HA) AF461521.1 A/chicken/Shandong/1/02(H9N2) neuraminidase (NA) AY295761.1 A/Chicken/Shanghai/F/98(H9N2) hemagglutinin AF461532.1 A/Chicken/Shanghai/1/02(H9N2) hemagglutinin AY281745.1 A/Chicken/Shanghai/2/99(H9N2)) hemagglutinin (HA) AF461522.1 A/Chicken/Shanghai/3/00(H9N2)) hemagglutinin (HA) AF461523.1 A/Chicken/Shanghai/F/98(H9N2) hemagglutinin (HA) AY743216.1 A/Chicken/Shanghai/4-2/01(H9N2) hemagglutinin (HA) AF461525.1 A/Chicken/Shanghai/4-1/01(H9N2) hemagglutinin (HA) AF461524.1 A/Chicken/Shanghai/4/01(H9N2) hemagglutinin (HA) AY083841.1 A/Chicken/Shanghai/3/01(H9N2) hemagglutinin HA) AY083840.1 A/chicken/Talmei_Elazar/1304/03(H9N2)nucleoprotein DQ116530.1 A/chicken/Talmei_Elazar/1304/03(H9N2) neuraminidase DQ116072.1 A/Chicken/Tianjing/2/96(H9N2) hemagglutinin AF461527.1 A/Chicken/Tianjing/1/96(H9N2) hemagglutinin (HA) AF461526.1 A/chicken/Tel Adashim/811/01(H9N2) hemagglutinin DQ104467.1 A/chicken/Tel Adashim/811/01(H9N2) nucleoprotein DQ116527.1 A/ck/Tel_Adashim/811/01(H9N2) neuraminidase DQ116064.1 A/chicken/Tel Adashim/812/01(H9N2) nucleoprotein DQ116528.1 A/chicken/Tel Adashim/812/01(H9N2) hemagglutinin DQ104468.1 A/ck/Tel_Adashim/812/01(H9N2) neuraminidase DQ116065.1 A/chicken/Tel Adashim/786/01(H9N2) nucleoprotein DQ116524.1 A/chicken/Tel Adashim/809/01(H9N2) hemagglutinin DQ104465.1 A/chicken/Tel Adashim/809/01(H9N2) nucleoprotein DQ116525.1 A/chicken/Tel Adashim/1469/03(H9N2) nucleoprotein DQ116507.1 A/chicken/Tel Adashim/1469/303(H9N2) hemagglutinin DQ104481.1 A/chicken/Tel Adashim/1506/03(H9N2) neuraminidase DQ116080.1 A/chicken/Tel Adashim/1506/03(H9N2) hemagglutinin DQ104474.1 A/chicken/Tel Adashim/1506/03(H9N2) nucleoprotein DQ116510.1 A/chicken/Tel Adashim/1332/03(H9N2) nucleoprotein DQ116501.1 A/chicken/Tel Adashim/1321/03(H9N2) nucleoprotein DQ116500.1 A/chicken/Tel Adashim/1332/03(H9N2) hemagglutinin DQ108907.1 A/chicken/Tel Adashim/1321/03(H9N2) hemagglutinin DQ108906.1 A/chicken/Telmond/1308/03(H9N2) nucleoprotein DQ116499.1 A/chicken/Telmond/1308/03(H9N2) neuraminidase DQ116073.1 A/chicken/Telmond/1308/03(H9N2) hemagglutinin DQ108921.1 A/chicken/Tzrofa/1568/04(H9N2) nucleoprotein DQ116519.1 A/chicken/Tzrofa/1568/04(H9N2) hemagglutinin DQ108919.1 A/chicken/UP/India/2544/2004(H9N2) polymerase basic 2 (PB2) DQ979864.1 A/chicken/UP/India/2543/2004(H9N2) polymerase basic 2 (PB2) DQ979863.1 A/chicken/Wangcheng/4/2001(H9N2) nucleoprotein AY268949.1 A/chicken/Ysodot/1362/03(H9N2) nucleoprotein DQ116502.1 A/chicken/Ysodot/1362/03(H9N2) hemagglutinin DQ108908.1 A/Chicken/Yunnan/2/00(H9N2) hemagglutinin (HA) AF461529.1 A/Chicken/Yunnan/1/99(H9N2) hemagglutinin (HA) AF461528.1 A/duck/Eastern China/01/2000(H9N2) segment 6 neuraminidase (NA) EU429725.1 A/duck/Eastern China/48/2001(H9N2) segment 6 neuraminidase (NA) EU429707.1 A/duck/Eastern China/66/2003(H9N2) segment 6 neuraminidase (NA) EU429699.1 A/duck/Eastern China/80/2004(H9N2) segment 6 neuraminidase (NA) EU429726.1 A/duck/Hong Kong/448/78(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107494.1 A/duck/Hong Kong/448/78(H9N2) hemagglutinin precursor AY206673.1 A/duck/Hong Kong/366/78(H9N2) hemagglutinin precursor AY206674.1 A/duck/Hong Kong/784/79(H9N2)) matrix protein 1 (M) and matrix protein 2 (M) DQ107496.1 A/duck/Hong Kong/702/79(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107495.1 /duck/Hong Kong/702/79(H9N2) hemagglutinin precursor AY206672.1 A/duck/Hong Kong/610/79(H9N2) hemagglutinin precursor AY206680.1 A/duck/Hong Kong/552/79(H9N2) hemagglutinin precursor AY206679.1 A/duck/Hong Kong/644/79(H9N2) hemagglutinin precursor AY206678.1 A/duck/Korea/S13/2003(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107518.1 A/duck/Nanchang/4-361/2001(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107511.1 A/duck/NY/83793/2002(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107499.1 A/goose/MN/5733-1243/80(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107492.1 A/geese/Tel Adashim/829/01(H9N2) hemagglutinin DQ104469.1 A/geese/Tel Adashim/830/01(H9N2 hemagglutinin DQ104470.1 A/ostrich/Eshkol/1436/03(H9N2) neuraminidase DQ116076.1 A/ostrich/Eshkol/1436/03(H9N2) nucleoprotein DQ116505.1 A/pigeon/Hong Kong/WF286/2000(H9N2) matrix protein 1 (M) and matrix protein DQ107509.1 2 (M) A/quail/Hong Kong/YU415/2002(H9N2) matrix protein 1 (M) and matrix protein 2 DQ107516.1 (M) A/quail/Hong Kong/SSP225/2001(H9) matrix protein 1 (M) and matrix protein 2 (M) DQ107512.1 A/quail/Hong Kong/YU1495/2000(H9N2) matrix protein 1 (M) and matrix protein DQ107510.1 2(M) A/quail/Hong Kong/A28945/88(H9N2) hemagglutinin precursor AY206675.1 A/shorebird/Delaware/276/99 (H9N2) nonfunctional matrix protein AY664464.1 A/shorebird/Delaware/113/2001(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107505.1 A/silky chicken/Hong Kong/WF266/2002(H9N2) matrix protein 2 (M) and matrix DQ107515.1 protein 1 (M) A/shorebird/Delaware/77/2001(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107497.1 A/guinea fowl/Hong Kong/WF10/99(H9N2) hemagglutinin precursor AY206676.1 A/swine/Hangzhou/1/2006(H9N2) nucleocapsid protein (NP) DQ907704.1 A/swine/Hangzhou/1/2006(H9N2)) matrix protein 1 (M1) EF055887.1 A/swine/Hangzhou/1/2006(H9N2)) nonstructural protein 1 (NS1) DQ823385.1 A/Sw/ShanDong/1/2003(H9N2) hemagglutinin (HA) AY294658.1 A/turkey/CA/6889/80(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107491.1 A/turkey/TX/28737/81(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107493.1 A/turkey/MN/511/78(H9N2) matrix protein 1 (M) and matrix protein 2 (M) DQ107490.1 A/turkey/Beit Herut/1267/03(H9N2) hemagglutinin DQ104485.1 A/turkey/Beit HaLevi/1009/02(H9N2) hemagglutinin DQ104473.1 A/turkey/Beit Herut/1265/03(H9N2) hemagglutinin DQ104456.1 A/turkey/Beit_HaLevi/1562/03(H9N2) nucleoprotein DQ116515.1 A/turkey/Beit_HaLevi/1566/04(H9N2) nucleoprotein DQ116517.1 A/turkey/Beit_HaLevi/1562/03(H9N2) neuraminidase DQ116083.1 A/turkey/Beit_HaLevi/1566/04(H9N2) neuraminidase DQ116084.1 A/turkey/Beit_Herut/1267/03(H9N2) neuraminidase DQ116070.1 A/turkey/Beit_Herut/1265/03(H9N2) neuraminidase DQ116069.1 A/turkey/Beit HaLevi/1566/04(H9N2) hemagglutinin DQ108917.1 A/turkey/Bezat/89/05(H9N2) hemagglutinin DQ108922.1 A/turkey/Brosh/1276/03(H9N2) hemagglutinin DQ104458.1 A/turkey/Brosh/1276/03(H9N2) neuraminidase DQ116071.1 A/turkey/Emek Hefer/1272/03(H9N2) hemagglutinin DQ104475.1 A/turkey/Ein Habsor/1804/04(H9N2) hemagglutinin DQ108924.1 A/turkey/Ein Tzurim/1172/02(H9N2) hemagglutinin DQ104451.1 A/turkey/Ein Tzurim/1738/04(H9N2) hemagglutinin DQ108920.1 A/turkey/Ein_Tzurim/1738/04(H9N2) neuraminidase DQ116085.1 A/turkey/Gyvat Haim Ehud/1544/03(H9N2)hemagglutinin DQ108913.1 A/turkey/Givat Haim/810/01 (H9N2) hemagglutinin DQ104466.1 A/turkey/Givat Haim/810/01 (H9N2) nucleoprotein DQ116526.1 A/turkey/Givat Haim/868/02(H9N2) hemagglutinin DQ104471.1 A/turkey/Givat Haim/622/02(H9N2) hemagglutinin DQ104462.1 A/turkey/Givat_Haim/965/02(H9N2) nucleoprotein DQ116498.1 A/turkey/Gyvat_Haim_Ehud/1544/03(H9N2) nucleoprotein DQ116513.1 A/turkey/Gyvat_Haim_Ehud/1544/03(H9N2) neuraminidase DQ116082.1 A/tk/Givat_Haim/810/25.12.01(H9N2) neuraminidase DQ116063.1 A/turkey/Givat_Haim/622/02(H9N2)) neuraminidase DQ116060.1 A/turkey/Givat_Haim/965/02(H9N2) neuraminidase DQ116057.1 A/turkey/Hod_Ezyon/699/02(H9N2) neuraminidase DQ116062.1 A/turkey/Mishmar Hasharon/619/02 (H9N2) hemagglutinin DQ104461.1 A/turkey/Mishmar_Hasharon/619/02(H9N2) neuraminidase DQ116059.1 A/turkey/Kfar_Vitkin/616/02(H9N2) neuraminidase DQ116058.1 A/turkey/Kfar Vitkin/616/02 (H9N2) hemagglutinin DQ104460.1 A/turkey/Kfar Vitkin/615/02 (H9N2)hemagglutinin DQ104459.1 A/turkey/Kfar Vitkin/615/02 (H9N2) nucleoprotein DQ116520.1 A/turkey/Kfar_Vitkin/616/02(H9N2)) nucleoprotein DQ116521.1 A/turkey/Kfar Warburg/1224/03(H9N2) hemagglutinin DQ104455.1 A/tk/Kfar_Vitkin/615/02(H9N)) neuraminidase DQ116067.1 A/turkey/Mishmar_Hasharon/619/02(H9N2) nucleoprotein DQ116522.1 A/turkey/Naharia/1013/02(H9N2) hemagglutinin DQ104449.1 A/turkey/Nahalal/1547/04(H9N2) hemagglutinin DQ108932.1 A/turkey/Neve Ilan/90710/00 (H9N2) nucleoprotein DQ116529.1 A/tk/Neve_Ilan/90710/00(H9N2) neuraminidase DQ116066.1 A/turkey/Qevuzat_Yavne/1242/03(H9N2) neuraminidase DQ116086.1 A/turkey/Sapir/1199/02(H9N2) hemagglutinin DQ104452.1 A/turkey/Shadmot Dvorah/1567/04(H9N2) nucleoprotein DQ116518.1 A/turkey/Shadmot Dvorah/1567/04(H9N2) hemagglutinin DQ108918.1 A/turkey/Tzur Moshe/1565/04(H9N2) nucleoprotein DQ116516.1 A/turkey/Tzur Moshe/1565/04(H9N2) hemagglutinin DQ108916.1 A/turkey/Yedidia/625/02 (H9N2) hemagglutinin DQ104463.1 A/turkey/Yedidia/625/02 (H9N2) nucleoprotein DQ116523.1 A/turkey/Yedidia/625/02 (H9N2) neuraminidase DQ116061.1 A/turkey/Yedidia/911/02(H9N2) hemagglutinin DQ104448.1 A/turkey/Avigdor/1215/03 (H9N2) hemagglutinin DQ104454.1 A/turkey/Avigdor/1209/03(H9N2) hemagglutinin DQ104453.1 A/turkey/Avichail/1075/02(H9N2) hemagglutinin DQ104450.1 A/turkey/Avigdor/1920/04(H9N2) hemagglutinin DQ108926.1 A/pintail/Alberta/49/2003(H9N5) matrix protein 1 (M) and matrix protein 2 (M) DQ107498.1 A/red knot/Delaware/2552/87 (H9N5) nonfunctional matrix protein AY664472.1 A/duck/Hong Kong/147/77(H9N6) hemagglutinin precursor AY206671.1 A/shorebird/Delaware/270/2001(H9N7) matrix protein 1 (M) and matrix protein 2 (M) DQ107504.1 A/shorebird/Delaware/277/2000(H9N7) matrix protein 1 (M) and matrix protein 2 (M) DQ107507.1 A/shorebird/Delaware/275/2001(H9N7)) matrix protein 2 (M) and matrix protein 1 (M) DQ107506.1 A/ruddy turnstone/Delaware/116/98 (H9N8) nonfunctional matrix protein AY664435.1 A/shorebird/Delaware/141/2002(H9N9) matrix protein 1 (M) and matrix protein 2 (M) DQ107503.1 A/ruddy turnstone/Delaware/103/2002(H9N9) matrix protein 1 (M) and matrix DQ107502.1 protein 2 (M) A/shorebird/Delaware/29/2002(H9N9) matrix protein 1 (M) and matrix protein 2 (M) DQ107501.1 A/shorebird/Delaware/18/2002(H9N9) matrix protein 1 (M) and matrix protein 2 (M) DQ107500.1 A/ruddy turnstone/Delaware/259/98 (H9N9) nonfunctional matrix protein AY664469.1 H10N* A/duck/Eastern China/527/2003(H10N3) segment 6 neuraminidase (NA) EU429716.1 A/duck/Eastern China/495/2003(H10N3) segment 6 neuraminidase (NA) EU429715.1 A/duck/Eastern China/372/2003(H10N3) segment 6 neuraminidase (NA) EU429714.1 A/duck/Eastern China/488/2003(H10N3) segment 6 neuraminidase (NA) EU429712.1 A/duck/Eastern China/453/2002(H10N3) segment 6 neuraminidase (NA) EU429711.1 A/duck/Eastern China/412/2003(H10N3) segment 6 neuraminidase (NA) EU429710.1 A/duck/Eastern China/404/2003(H10N3) segment 6 neuraminidase (NA) EU429709.1 A/duck/Eastern China/397/2003(H10N3) segment 6 neuraminidase (NA) EU429708.1 A/duck/Eastern China/502/2003(H10N3) segment 6 neuraminidase (NA) EU429705.1 A/duck/Eastern China/395/2003(H10N3) segment 6 neuraminidase (NA) EU429704.1 A/duck/Eastern China/356/2003(H10N3) segment 6 neuraminidase (NA) EU429703.1 A/duck/Eastern China/368/2003(H10N3) segment 6 neuraminidase (NA) EU429702.1 A/chicken/Singapore/1993(H10N5) M2 protein EU014145.1 A/red knot/Delaware/2561/87 (H10N5) nonfunctional matrix protein AY664441.1 A/chicken/Germany/N/1949(H10N7) segment 6 neuraminidase (NA) EU429796.1 A/ruddy turnstone/Delaware/2764/87 (H10N7) nonfunctional matrix protein AY664462.1 A/mallard/Alberta/71/98 (H10N7) nonfunctional matrix protein AY664485.1 A/mallard/Alberta/90/97 (H10N7) nonfunctional matrix protein AY664446.1 A/mallard/Alberta/110/99(H10N7) nonfunctional matrix protein AY664481.1 A/mallard/Alberta/297/77 (H10N7) nonfunctional matrix protein AY664430.1 A/mallard/Alberta/223/98 (H10N8) nonfunctional matrix protein AY664486.1 H11N* A/ruddy turnstone/New Jersey/51/85 (H11N1) nonfunctional matrix protein AY664479.1 A/duck/Nanchang/1749/1992(H11N2) nucleoprotein (NP) U49094.1 A/duck/Hong Kong/62/1976(H11N2) polymerase (PB1) U48280.1 A/duck/Yangzhou/906/2002(H11N2) hemagglutinin DQ080993.1 A/shorebird/Delaware/86/99 (H11N2) nonfunctional matrix protein AY664463.1 A/ruddy turnstone/Delaware Bay/2762/1987(H11N2)polymerase PB2 (PB2) CY126279.1 A/ruddy turnstone/Delaware/2762/87 (H11N2) nonfunctional matrix protein AY664459.1 A/ruddy turnstone/Delaware Bay/2762/1987(H11N2) polymerase PB1 (PB1) and CY126278.1 PB1-F2 protein (PB1-F2) A/ruddy turnstone/Delaware/2589/87 (H11N4) nonfunctional matrix protein AY664478.1 A/duck/England/1/1956(H11N6) segment 6 neuraminidase (NA) EU429795.1 A/mallard/Alberta/125/99 (H11N6) nonfunctional matrix protein AY664483.1 A/duck/Memphis/546/1974(H11N9) segment 6 neuraminidase (NA) EU429798.1 A/mallard/Alberta/122/99 (H11N9) nonfunctional matrix protein AY664444.1 H12N* A/Mallard Duck/Alberta/342/83(H12N1) segment 4 hemagglutinin (HA1) AF310991.1 A/ruddy turnstone/Delaware/67/98(H12N4) nonfunctional matrix protein AY664470.1 A/Ruddy Turnstone/Delaware/67/98(H12N4) segment 4 hemagglutinin (HA1) AF310990.1 A/mallard/Alberta/52/97 (H12N5) nonfunctional matrix protein AY664448.1 A/mallard/Alberta/223/77 (H12N5) nonfunctional matrix protein AY664431.1 A/Laughing Gull/New Jersey/171/92(H12N5) segment 4 hemagglutinin (HA1) AF310992.1 A/ruddy turnstone/Delaware/265/98 (H12N8) nonfunctional matrix protein AY664438.1 H13N* A/herring gull/New Jersey/782/86 (H13N2) nonfunctional matrix protein AY664475.1 A/shorebird/Delaware/224/97 (H13N6) nonfunctional matrix protein AY664421.1 Other A/PR/8/34 (H1N1) x A/England/939/69 (H3N2) PB1 protein AJ564806.1 A/PR/8/34 (H1N1) x A/England/939/69 (H3N2)PB2 protein AJ564804.1 A/duck/Czechslovakia/56(H4N6) x A/USSR/90/77(H1N1)) neuraminidase (NA) EU643639.1 A/duck/Czechslovakia/56(H4N6) x A/USSR/90/77(H1N1)) neuraminidase (NA) EU643638.1 A/duck/Ukraine/63(H3N8) x A/USSR/90/77(H1N1)) neuraminidase (NA) EU643637.1 A/duck/Ukraine/63(H3N8) x A/USSR/90/77(H1N1)) neuraminidase (NA) EU643636.1 RCB1-XXI: A/USSR/90/77(H1N1)xA/Duck/Czechoslov 56 (H4N6) segment 4 AF290438.1 hemagglutinin RCB1: A/USSR/90/77(H1N1)xA/Duck/Czechoslov 56 (H4N6) hemagglutinin AF290437.1 PX14-XIII (A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3)) AF290442.1 segment 4 hemagglutinin PX14(A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3)) segment 4 AF290441.1 hemagglutinin PX8-XIII(A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3)) segment 4 hemagglutinin PX8 (A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3)) segment 4 AF290439.1 hemagglutinin A/swine/Schleswig-Holstein/1/93 hemagglutinin (HA) U72669.1 A/swine/England/283902/93 hemagglutinin (HA) U72668.1 A/swine/England/195852/92 hemagglutinin (HA) U72667.1 A/swine/England/117316/86 hemagglutinin (HA) U72666.1 A/turkey/Germany/2482/90) hemagglutinin (HA) U96766.1

TABLE 11 Influenza B Antigens GenBank Strain/Protein Access No. B/Daeku/47/97 hemagglutinin AF521237.1 B/Daeku/45/97 hemagglutinin AF521236.1 B/Daeku/10/97 hemagglutinin AF521221.1 B/Daeku/9/97 hemagglutinin AF521220.1 B/Gyeonggi/592/2005 neuraminidase DQ231543.1 B/Gyeonggi/592/2005 hemagglutinin DQ231538.1 B/Hong Kong/5/72 neuraminidase AF305220.1 B/Hong Kong/5/72 hemagglutinin AF305219.1 B/Hong Kong/157/99 hemagglutinin AF387503.1 B/Hong Kong/157/99 hemagglutinin AF387502.1 B/Hong Kong/156/99 hemagglutinin AF387501.1 B/Hong Kong/156/99 hemagglutinin AF387500.1 B/Hong Kong/147/99 hemagglutinin AF387499.1 B/Hong Kong/147/99 hemagglutinin AF387498.1 B/Hong Kong/110/99 hemagglutinin AF387497.1 B/Hong Kong/110/99 hemagglutinin AF387496.1 B/Incheon/297/2005 hemagglutinin DQ231539.1 B/Incheon/297/2005 neuraminidase DQ231542.1 B/Lee/40 polymerase protein (PB1) D00004.1 B/Michigan/22572/99 hemagglutinin AY129961.1 B/Michigan/22723/99 hemagglutinin (HA) AY112992.1 B/Michigan/22631/99 hemagglutinin (HA) AY112991.1 B/Michigan/22587/99 hemagglutinin (HA) AY112990.1 B/New York/20139/99 hemagglutinin AY129960.1 B/Panama/45/90 nucleoprotein AF005739.1 B/Panama/45/90 polymerase (PA) AF005738.1 B/Panama/45/90 polymerase (PB2) AF005737.1 B/Panama/45/90 polymerase (PB1) AF005736.1 B/Pusan/250/99 hemagglutinin AF521218.1 B/Pusan/255/99 hemagglutinin AF521226.1 B/Pusan/270/99 hemagglutinin AF521219.1 B/Pusan/285/99 hemagglutinin AF521217.1 B/Riyadh/01/2007 segment 8 nuclear export GU135839.1 protein (NEP) and non structural protein 1 (NS1) B/Seoul/6/88 hemagglutinin AF521238.1 B/Seoul/12/88 hemagglutinin AF521239.1 B/Seoul/1/89 hemagglutinin AF521230.1 B/Seoul/37/91 hemagglutinin AF521229.1 B/Seoul/38/91 hemagglutinin AF521227.1 B/Seoul/40/91 hemagglutinin AF521235.1 B/Seoul/41/91 hemagglutinin AF521228.1 B/Seoul/13/95 hemagglutinin AF521225.1 B/Seoul/12/95 hemagglutinin AF521223.1 B/Seoul/17/95 hemagglutinin AF521222.1 B/Seoul/21/95 hemagglutinin AF521224.1 B/Seoul/16/97 hemagglutinin AF521233.1 B/Seoul/19/97 hemagglutinin AF521231.1 B/Seoul/28/97 hemagglutinin AF521234.1 B/Seoul/31/97 hemagglutinin AF521232.1 B/Seoul/232/2004 neuraminidase DQ231541.1 B/Seoul/1163/2004 neuraminidase DQ231540.1 B/Seoul/1163/2004 hemagglutinin DQ231537.1 B/Sichuan/379/99 hemagglutinin (HA) AF319590.1 B/Sichuan/38/2000 hemagglutinin (HA) AF319589.1 B/South Carolina/25723/99 hemagglutinin AY129962.1 B/Switzerland/4291/97 hemagglutinin AF387505.1 B/Switzerland/4291/97 hemagglutinin AF387504.1 B/Taiwan/21706/97 nonstructural protein 1 (NS1) AF492479.1 B/Taiwan/21706/97 hemagglutinin (HA) AF026162.1 B/Taiwan/3143/97 nonstructural protein 1 (NS1) AF492478.1 B/Taiwan/3143/97 haemagglutinin (HA) AF026161.1 B/Taiwan/2026/99 nonstructural protein 1 (NS1) AF492481.1 B/Taiwan/2026/99 hemagglutinin AY604741.1 B/Taiwan/2027/99 nonstructural protein 1 (NS1) AF492480.1 B/Taiwan/2027/99 hemagglutinin AY604742.1 B/Taiwan/1243/99 nonstructural protein NS1(NS1) AF380504.1 B/Taiwan/1243/99 hemagglutinin AY604740.1 B/Taiwan/2195/99 hemagglutinin AY604743.1 B/Taiwan/2195/99 nonstructural protein 1 (NS1) AF492482.1 B/Taiwan/1293/2000 nonstructural protein NS 1 (NS 1) AF380509.1 B/Taiwan/1293/00 hemagglutinin AY604746.1 B/Taiwan/1293/2000 hemagglutinin (HA) AF492477.1 B/Taiwan/1265/2000 nonstructural protein NS1 (NS1) AF380508.1 B/Taiwan/1265/00 hemagglutinin AY604745.1 B/Taiwan/4184/2000 nonstructural protein NS1 (NS1) AF380507.1 B/Taiwan/4184/00 hemagglutinin (HA) AY604750.1 B/Taiwan/31511/2000 nonstructural protein NS1 (NS1) AF380505.1 B/Taiwan/31511/00 hemagglutinin (HA) AY604748.1 B/Taiwan/12192/2000 hemagglutinin AY604747.1 B/Taiwan/41010/00 hemagglutinin (HA) AY604749.1 B/Taiwan/41010/2000 nonstructural protein NS1 (NS1) AF380506.1 B/Taiwan/0409/00 hemagglutinin (HA) AY604744.1 B/Taiwan/202/2001 nonstructural protein 1 (NS1) AF380512.1 B/Taiwan/202/2001 hemagglutinin (HA) AF366076.1 B/Taiwan/11515/2001 nonstructural protein 1 (NS1) AF380511.1 B/Taiwan/11515/01 hemagglutinin AY604754.1 B/Taiwan/11515/2001 hemagglutinin (HA) AF366075.1 B/Taiwan/1103/2001 nonstructural protein NS1 (NS1) AF380510.1 B/Taiwan/1103/01 hemagglutinin AY604755.1 B/Taiwan/114/2001 hemagglutinin (HA), HA-4 allele AF492476.1 B/Taiwan/2805/2001 hemagglutinin (HA) AF400581.1 B/Taiwan/2805/01 hemagglutinin (HA) AY604752.1 B/Taiwan/0114/01 hemagglutinin (HA) AY604753.1 B/Taiwan/0202/01 hemagglutinin (HA) AY604751.1 B/Taiwan/4119/02 hemagglutinin (HA) AY604778.1 B/Taiwan/4602/02 hemagglutinin (HA) AY604777.1 B/Taiwan/1950 /02 hemagglutinin (HA) AY604776.1 B/Taiwan/1949/02 hemagglutinin (HA) AY604775.1 B/Taiwan/1584 /02 hemagglutinin (HA) AY604774.1 B/Taiwan/1561 /02 hemagglutinin (HA) AY604773.1 B/Taiwan/ 1536/02 hemagglutinin (HA) AY604772.1 B/Taiwan/1534 /02 hemagglutinin (HA) AY604771.1 B/Taiwan/1503 /02 hemagglutinin (HA) AY604770.1 B/Taiwan/1502/02 hemagglutinin (HA) AY604769.1 B/Taiwan/1013 /02 hemagglutinin (HA) AY604768.1 B/Taiwan/0993 /02 hemagglutinin (HA) AY604766.1 B/Taiwan/0932 /02 hemagglutinin (HA) AY604765.1 B/Taiwan/0927/02 hemagglutinin (HA) AY604764.1 B/Taiwan/0880 /02 hemagglutinin (HA) AY604763.1 B/Taiwan/0874/02 hemagglutinin (HA) AY604762.1 B/Taiwan/0730 /02 hemagglutinin (HA) AY604761.1 B/Taiwan/0722/02 hemagglutinin (HA) AY604760.1 B/Taiwan/0702 /02 hemagglutinin (HA) AY604759.1 B/Taiwan/0654/02 hemagglutinin (HA) AY604758.1 B/Taiwan/0600/02 hemagglutinin (HA) AY604757.1 B/Taiwan/0409 /02 hemagglutinin (HA) AY604756.1 B/Taiwan/0879/02 nonfunctional hemagglutinin AY604767.1 B/Taiwan/ 3532/03 hemagglutinin (HA) AY604794.1 B/Taiwan/2551 /03 hemagglutinin (HA) AY604793.1 B/Taiwan/ 1618/03 hemagglutinin (HA) AY604792.1 B/Taiwan/ 1574/03 hemagglutinin (HA) AY604791.1 B/Taiwan/1013 /03 hemagglutinin (HA) AY604790.1 B/Taiwan/0833 /03 hemagglutinin (HA) AY604789.1 B/Taiwan/0735 /03 hemagglutinin (HA) AY604788.1 B/Taiwan/0699/03 hemagglutinin (HA) AY604787.1 B/Taiwan/0684/03 hemagglutinin (HA) AY604786.1 B/Taiwan/0616 /03 hemagglutinin (HA) AY604785.1 B/Taiwan/0615 /03 hemagglutinin (HA) AY604784.1 B/Taiwan/0610 /03 hemagglutinin (HA) AY604783.1 B/Taiwan/0576 /03 hemagglutinin (HA) AY604782.1 B/Taiwan/0569/03 hemagglutinin (HA) AY604781.1 B/Taiwan/0562/03 hemagglutinin (HA) AY604780.1 B/Taiwan/0002 /03 hemagglutinin (HA) AY604779.1 B/Taiwan/773/2004 hemagglutinin (HA) EU068195.1 B/Taiwan/187/2004 hemagglutinin (HA) EU068194.1 B/Taiwan/3892/2004 hemagglutinin (HA) EU068193.1 B/Taiwan/562/2004 hemagglutinin (HA) EU068191.1 B/Taiwan/234/2004 hemagglutinin (HA) EU068188.1 B/Taiwan/4897/2004 hemagglutinin (HA) EU068186.1 B/Taiwan/8579/2004 hemagglutinin (HA) EU068184.1 B/Taiwan/184/2004 hemagglutinin (HA) EU068183.1 B/Taiwan/647/2005 hemagglutinin (HA) EU068196.1 B/Taiwan/877/2005 hemagglutinin (HA) EU068198.1 B/Taiwan/521/2005 hemagglutinin (HA) EU068189.1 B/Taiwan/1064/2005 hemagglutinin (HA) EU068192.1 B/Taiwan/3722/2005 hemagglutinin (HA) EU068197.1 B/Taiwan/5049/2005 hemagglutinin (HA) EU068190.1 B/Taiwan/5011/2005 hemagglutinin (HA) EU068187.1 B/Taiwan/4659/2005 hemagglutinin (HA) EU068185.1 B/Taiwan/25/2005 hemagglutinin (HA) EU068182.1 B/Taiwan/1037/2005 hemagglutinin (HA) EU068181.1 B/Taiwan/62/2005 hemagglutinin (HA) EU068180.1 B/Taiwan/591/2005 hemagglutinin (HA) EU068179.1 B/Taiwan/649/2005 hemagglutinin (HA) EU068178.1 B/Taiwan/4554/2005 hemagglutinin (HA) EU068177.1 B/Taiwan/987/2005 hemagglutinin (HA) EU068176.1 B/Taiwan/2607/2006 hemagglutinin (HA) EU068175.1 B/Vienna/1/99 hemagglutinin AF387495.1 B/Vienna/1/99 hemagglutinin AF387494.1 B/Vienna/1/99 hemagglutinin AF387493.1 B/Vienna/1/99 hemagglutinin AF387492.1

TABLE 12 Influenza C Antigens GenBank Strain/Protein Access No. C/JHB/1/66) hemagglutinin-esterase-fusion protein AY880247.1 (HEF) mRNA, complete cds. STRAIN C/ANN ARBOR/1/50) persistent variant AF102027.1 segment 7 non-structural protein 1 (NS1) mRNA, complete cds (STRAIN C/ANN ARBOR/1/50) wild type segment 7 AF102026.1 non-structural protein 1 (NS1) mRNA, complete cds (C/JHB/1/66) hemagglutinin-esterase-fusion AY880247.1 protein (HEF) mRNA, complete cds (STRAIN C/BERLIN/1/85) mRNA for X55992.1 basic polymerase 2 precursor

TABLE 13 H7 Hemagglutinin Amino Acid Sequences SEQ ID Accession No/ NO Strain/Protein Amino Acid Sequence 1 AAM19228A/ ACVLVEAKGDKICLGHHAVVNGTKVNTLTEKGIEVVNAT turkey/Minnesota/ ETVETANIGKICTQGKRPTDLGQCGLLGTLIGPPQCDQFLE 38429/1988 FESDLIIERREGNDVCYPGKFTNEESLRQILRGSGGIDKESM 1988//HA GFTYSGIITNGATSACRRSGSSFYAEMKWLLSNSDNAAFP 20335017 QMTKSYRNPRNKPALIVWGIHHSGSTTEQTKLYGSGNKLI TVESSKYQQSFTPSPGARPQVNGESGRIDFHWMLLDPNDT VTFTFNGAFIAPDRASFFKGESLGVQSDVPLDSSCGGDCFH SGGTIVSSLPFQNINPRTVGKCPRYVKQPSLLLATGMRNVP ENPKTRGLFGAIAGFIEKDGGSHYG 2 AAY46211A/ MNTQILVFALVAIIPINADKICLGHHAVSNGTKVNTLTERG mallard/Sweden/ VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP 91/2002 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2002//HA GGIDKETMGFTYSGIRTNGAPSACRRSGSSFYAEMKWLLS 66394828 NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI 3 ABI84694A/ MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE turkey/Minnesota/ KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG 1/1988 PPQCDQFLEFESDLIIERREGNDVCYPGKFTNEESLRQILRG 1988/07/13 HA SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 115278573 SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN QHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHAQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 4 AB S89409 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/blue-winged GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP teal/Ohio/566/ PQCDQFLEFDTDLIIERREGTDVCYPGKFTNEESLRQILRGS 20062006//HA GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 155016324 NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKL YGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHW LLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDS GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD DQCMESIRNNTYDHTQYRTESLQNRIQIDPVRLSSGYKDII LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 5 ACD03594A/ MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTE ruddy KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG turnstone/DE/ PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG 1538/20002000// SGGIDKESMGFTYSGIRTNGATSACRRLGSSFYAEMKWLL HA 187384848 SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI 6 BAH22785A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER duck/Mongolia/ GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP 119/2008 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2008//HA GGIGKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 223717820 NTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRTVGKCPRYVKQESLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 7 CAY39406A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER Anascrecca/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Spain/14 PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 60/2008 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2008/01/26 HA SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK 254674376 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LMLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFTEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 8 ACX53683A/ MNIQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERG goose/Czech VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP Republic/1848- PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE K9/2009 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2009/02/04 HA SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK 260907763 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 9 ACZ48625A/ MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE turkey/Minnesota/ KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG 38429/1988 PPQCDQFLEFESDLIIERREGNDVCYPGKFTNEESLRQILRG 1988//HA SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 269826341 SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE L 10 ADC29485A/ STQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGNVI mallard/Spain/ NWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNKLY 08.00991.3/2005  ERVKRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTYD 2005/11/HA HSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFILL 284927336 11 ADK71137A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER blue-winged GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP teal/Guatemala/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG CIP049-01/2008 SGGIDKESMGFTYSGIRTNGATSACRRSGSSSYAEMKWLL 2008/02/07 HA SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTK 301333785 LYGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLD SGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLL LATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQHFE LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDI ILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 12 ADK71148A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER blue-winged GIEVVNXTETVETANIKKICTHGKRPTDLGQCGLLGTLIGP teal/Guatemala/ PQCDRFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRGS CIP049-02/2008 GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2008/03/05 HA NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKL 301333804 YGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFHW LLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLDS GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD DQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDII LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 13 ADN34727A/ MNIQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERG goose/Czech VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP Republic/1848- PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE T14/2009 SGGIDKETMGFTYSGIRTNGXTSACRRSGSSFYAEMKWLL 2009/02/04 HA SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK 307141869 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 14 AEK84760A/ PAFIAPDRASFLRGKSMGIQSGVQVDASCEGDCYHSGGTII wild SNLPFQNINSRAVGKCPRYVKQESLMLATGMKNVPELPK bird/Korea/A14/ GRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQGEGTAAD 2011 2011/02/ YKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGN HA 341610308 VINWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNK LYERVRRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTY DHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFIL LAIAMGLVFICVKNGNMRCTICI 15 AEK84761A/ ILVFALVAIIPTNANKIGLGHHAVSNGTKVNTLTERGVEVF wild NATETVERTNVPRICSKGKKTVDLGQCGLRGTITGPPQCD bird/Korea/A3/ QFLKFSPDLIIERQKGSDVCYPGKFVNEKPLRQILRESGGID 2011 2011/02/ KETMGFAYNGIKTNGPPIACRKSGSSFYAKMKWLLSNTD HA 341610310 KAAFPQMTKSYKNTRRNPALIVWGIHHSGSTTKQTKLYGI GSNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN PNDTVTFSFNGAFIPPDRASFLRGKSMGIQSGVQVDASCEG DCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATG MKNVPELPKGKGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTI DLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 16 AEK84763A/ ILVFALVAIIPTNANKIGLGHHAVSNGTKVNTLTERGVEFF wild NATETVEPTNVPRICSKGKKTVDLGQCGLLGTITGPPQCD bird/Korea/A9/ QFLEFSADLIIERREGSDVCYPGKFVNEKALRQILRESGGID 2011 2011/02/ KETMGFAYSGIKTNGPPIACRKSGSSFYAKMKWLLSNTDK HA 341610314 AAFPQMTKSYKNIRRDPALIVWGIHHSGSTTKQTNLYGIG SNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNP NDTVTFIFNGAFIAPDRASFLIGKSMGIQSGVQVDASCEGD CYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATGM KNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNA QGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEF TEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID LADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIAMGLVFICVKNGNMRCTICI 17 AEK84765A/ LVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVV spot-billed NATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQCD duck/Korea/447/ QFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGID 2011 2011/04/ KETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD HA 341610318 NAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTKLYGS GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN PNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDASCE GDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLAT GMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQ NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN EFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHT IDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD CMARIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 18 AEM98291A/ SILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV wild VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC duck/Mongolia/ DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI 1-241/2008 DKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT 2008/04/ HA DNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKLYG 344196120 SGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLM LNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDAN CEGDCYHSGGSIISNLPFQNINSRAVGKCPRYVKQESLML ATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSGYKD VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI 19 AFM09439A/ QILAFIACMLIGAKGDKICLGHHAVANGTKVNTLTERGIE emperor VVNATETVETVNIKKICTQGKRPTDLGQCGLLGTLIGPPQC goose/Alaska/ DQFLEFDADLIIERRKGTDVCYPGKFTNEESLRQILRGSGGI 44063-061/2006 DKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSD 2006/05/23 HA NAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKLYGS 390535062 GNKLITVGSSKYQQSFVPSPGARPQVNGQSGRIDFHWLLL DPNDTVTFTFNGAFIAPERASFFRGESLGVQSDVPLDSGCE GDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATG MRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNE FSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID LADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQC MESIRNNTYDHTQYRTESLQNRIQINPVKLSSGYKDIILWF SFGASCFLLLAIAMGLVFICIKNGNMRCTICI 20 AFV33945A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER guinea RIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP fowl/Nebraska/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG 17096-1/2011 SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/04/05 HA SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT 409676820 KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 21 AFV33947A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER goose/Nebraska/ GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP 17097-4/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG 2011 SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/04/05 HA SNSDNAAFPQMTKSYRNPRNKPALIVWGVHHSASATEQT 409676827 KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 22 AFX85260A/ MNTQILAFIACMLIGINGDKICLGHHAVANGTKVNTLTER ruddy GIEVVNATETVETANIKRICTQGKRPIDLGQCGLLGTLIGPP turnstone/ QCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRGS Delaware GGIDKESMGFTYSGIRTNGATSACIRLGSSFYAEMKWLLS Bay/220/1995 NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQTK 1995/05/21 HA LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH 423514912 WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGRCPRYVKQTSL LLATGMKNVPENPKTRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQF ELIDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 23 AGE08098A/ MNTQILTLIACMLIGAKGDKICLGHHAVANGTKVNTLTER northern GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP shoverl/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG Mississippi/ SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 110S145/ SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTK 2011 2011/01/08 LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH HA 444344488  WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHNGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 24 AGI60301A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Hangzhou/1/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 20132013/03/24 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 475662454 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGISGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 25 AGI60292A/ MNTQILVFALIAIIPANADKICLGHHAVSNGTKVNTLTERG Shanghai/466 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 4T/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/03/05 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 476403560 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCHHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 26 AGJ72861A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/ GEVVNATETVERTNIPRICSKGKKTVDLGQGGPRGTITGPP Zhejiang/DTID- QCDQFLEFSADLIMERREGSDVCYPGKFVNEEALRQILRES ZJU01/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/04/ HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 479280294 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 27 AGJ73503A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Nanjing/1/201 VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 32013/03/28 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 479285761 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 28 BAN16711A/ MNTQVLVFALMAIIPTNADKICLGHHAVSNGTKVNTLTER duck/Gunma/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG 466/2011 2011// PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE HA 482661571 SGGIDKETMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLL SNTDNAAFPQMTKSYKNTRRDPALIAWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDDTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 29 AGK84857A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Hangzhou/2/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 20132013/04/01 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 485649824 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQITKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 30 AGL44438A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shanghai/02/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013 2013/03/05 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 496493389 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 31 AGL33692A/ GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR Shanghai/465 LIEKTNQQFELIDNEFTEVEKQIGNVINWTRDSITEVWSYN 5T/2013 AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG 2013/02/26 HA TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID 491874175 PVKLSSGYKDVILWFSFGASCFILLAIAMGLVFICVKNGN MRCTICI 32 AGL33693A/ GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR Shanghai/465 LIEKTNQQFELIDNEFNEVEKQIGNVINWTRDSITEVWSYN 9T/2013 AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG 2013/02/27 HA TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID 491874186 PVKLSSGYKDVILWFSFGASCFILLAIVMGLVFICVKNGN MRCTICI 33 AGL95088A/ VFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN Taiwan/S020 ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF 76/2013 LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE 2013/04/22 HA AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA 501485301 AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIVMGLVFICVKNGNMR 34 AGL95098A/ LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN Taiwan/T020 ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF 81/2013 LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE 2013/04/22 HA AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA 501485319 AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIVMGLVFICVKNGNMRCT 35 AGM53883A/ GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ Shanghai/508 FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM 3T/2013 ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH 2013/04/20 HA KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG 507593986 YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCT 36 AGM53884A/ AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE Shanghai/518 FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID 0T/2013 LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC 2013/04/23 HA MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW 507593988 FSFGASCFILLAIVMGLVFICVKNGNMRCTICI 37 AGM53885A/ QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID Shanghai/524 NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH 0T/2013 TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD 2013/04/25 HA DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI 507593990 LWFSFGASCFILLAIVMGLVFICVKNGNMRCT 38 AGM53886A/ NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN Shanghai/484 EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI 2T/2013 DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD 2013/04/13 HA CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL 507593992 WFSFGASCFILLAIVMGLVFICVKNGNMRCT 39 AGM53887A/ NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN Shanghai/470 EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI 1T/2013 DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD 2013/04/06 HA CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL 507593994 WFSFGASCFILLAIVMGLVFICVKNGNMRCTIC 40 AGN69462A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Wuxi/2/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/03/31 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 511105778 GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 41 AGN69474A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Wuxi/1/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/03/31 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 511105798 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLINGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 42 AG051387A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Jiangsu/2/201 VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 32013/04/20 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 514390990 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRXEAMXBXIQIDPVKLSSGY KDVXJWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 43 BAN59726A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER duck/Mongolia/ GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP 147/2008 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2008/08/29 HA GGIGKETMGFTYSGIRTNGATSACRRSRSSFYAEMKWLLS 519661951 NTDNAAFPQMTRSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRTVGKCPRYVKQESLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 44 BAN59727A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER duck/Mongolia/ GVEVVNATETVERINVPRICSKGKRTVDLGQCGLLGTITG 129/2010 PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2010//HA SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 519661954 SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 45 AGQ80952A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER duck/Jiangxi/ GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP 3096/2009 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2009//HA GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 523788794 NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRAVGKCPRYVKQESL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 46 AGQ80989A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER duck/Jiangxi/ GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP 3257/2009 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2009//HA GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 523788868 NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGXSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRAVGKCPRYVKQESL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 47 AGQ81043A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Rizhao/515/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013//HA GGIDKEEMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 523788976 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 48 AGR33894A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Rizhao/719b/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013//HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 524845213 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDRSKYREEAMQNRXXXXXXXXXXX XKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 49 AGR49399A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP SD001/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2013/05/03 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 525338528 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 50 AGR49495A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shanghai/ VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP S1358/201 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 32013/04/03 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 525338689 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIKNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 51 AGR49506A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP S1410/201 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 32013/04/03 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 525338708 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 52 AGR49554A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Zhejiang/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP SD033/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/11 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 525338789 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVRRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 53 AGR49566A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG duck/Anhui/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP SC702/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/16 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 525338809 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 54 AGR49722A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG homing VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP pigeon/Jiangsu/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES SD184/2013 GGIDKEAMGFTYSEIRTNGATSACRRSGSSFYAEMKWLLS 2013/04/20 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 525339071 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 55 AGR49734A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG pigeon/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP S1069/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/02 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 525339091 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTITFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 56 AGR49770A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG wild VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP pigeon/Jiangsu/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES SD001/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/04/17 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 525339151 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 57 AGY41893A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Huizhou/01/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 20132013/08/08 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 552049496 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 58 AGY42258A/ FALVAIIPINADKICLGHHAVSNGTKVNTLTERGVEVVNA mallard/Sweden/ TETVERTNVPRICSRGKRTVDLGQCGLLGTIXGPPQCDQFL 91/2002 EFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKET 2002/12/12 HA MGFTYSGIRTNGAXSACRRSGSSFYAEMKWLLSNTDNAA 552052155 FPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKLYGSGNK LITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNPND TVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDANCEGDC YHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLLATGMK NVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG EGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTE VEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTIDLA DSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDCMA SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF GASCFILLAIAMGLVFMCVKNGNMRCTICI 59 AHA11441A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER guinea GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP fowl/Nebraska/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG 17096/2011 SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/04/10 HA SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT 557478572 KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 60 AHA11452A/ MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE turkey/Minnesota/ RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG 32710/2011 PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR 2011/07/12 HA GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL 557478591 LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FEMIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 61 AHA11461A/ MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE turkey/Minnesota/ RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG 31900/2011 PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR 2011/07/05 HA GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL 557478606 LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 62 AHK10585A/chicken/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Guangdong/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP G1/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/05/05 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 587680636 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 63 AGG53366A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER wild GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG duck/Korea/CS PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE M42-34/2011 SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/03/ HA SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK 459252887 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 64 AGG53377A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER wild GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG duck/Korea/CS PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE M42-1/2011 SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/03/ HA SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK 459252925 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT 65 AGG53399A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER wild GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG duck/Korea/MH PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE C39-26/2011 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/03/ HA SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK 459253005 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 66 AGG53432A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER wild GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG duck/Korea/MH PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE C35-41/2011 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/03/ HA SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK 459253136 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT 67 AGG53476A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER wild GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG duck/Korea/S H1 PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 9-27/2010 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2010/12/ HA SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK 459253257 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI 68 AGG53487A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER wild GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG duck/Korea/S H1 PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 9-50/2010 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2010/01/ HA SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK 459253278 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 69 AGG53520A/ QILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV wild VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC duck/Korea/SH2 DQLLEFSADLIIERREGTDVCYPGKFVNEEALRQILRESGGI 0-27/2008 EKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD 2008/12/ HA NAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKLYGS 459253409 GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLML NPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANC EGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLA TGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH TIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSGYKDVI LWFSFGASCFILLAIAMGLVFICVKNGNMR 70 AGL43637A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Taiwan/1/201 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 32013//HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 496297389 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGPSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIINNLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 71 AGL97639A/ IACMLVGAKGDKICLGHHAVANGTKVNTLTERGIEVVNA mallard/ TETVETANIKKLCTQGKRPTDLGQCGLLGTLIGPPQCDQFL Minnesota/AI09- EFDADLIIERREGTDVCYPGKFTNEESLRQILRGSGGIDKES 3770/2009 MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSDNAA 2009/09/12 HA FPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKLYGSGNK 505555371 LITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHWLLLDPN DTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDSGCEGDC FHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATGMRN VPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG EGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNEFSEI EQQIGNVINWTRDSMTELWSYNAELLVAMENQHTIDLAD SEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQCMESI RNNTYDHTQYRTESLQNRIQIDPVKLS 72 AG002477A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Xuzhou/1/201 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 32013/04/25 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 512403688 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 73 AGR84942A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Suzhou/5/201 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 32013/04/12 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304561 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 74 AGR84954A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Nanjing/6/201 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 32013/04/11 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304594 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNRNMRCTICI 75 AGR84978A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Wuxi/4/2013 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2013/04/07 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 526304656 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 76 AGR84990A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Wuxi/3/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/04/07 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 526304688 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 77 AGR85002A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Zhenjiang/1/2 VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 013 2013/04/07 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304708 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNKRCTICI 78 AGR85026A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Nanjing/2/201 VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 32013/04/05 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304762  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 79 AGU02230A/ LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVN Zhejiang/DTI ATETVERTNIPRICSKGKRTVDLGQCGLRGTITGPPQCDQF D-ZJU05/2013 LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE 2013/04/ HA AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA 532808765 AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIVMGLVFICVKNGNMRCT 80 AGU02233A/ FALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVNAT Zhejiang/DTI ETVERTNFPRICSKGKRTVDLGQCGLRGTITGPPQCDQFLE D-ZJU08/2013 FSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEA 2013/04/ HA MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNAA 532808788 FPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNK LVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD CYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATGM KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN EVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTIDLA DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF GASCFILLAIVMGLVFICVKNGNMRCT 81 AGW82588A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG tree VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP sparrow/Shanghai/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 01/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/05/09 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 546235348 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTIGI 82 AGW82600A/ ALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVNATE Shanghai/CN TVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQFLEF 01/2013 SADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEAM 2013/04/11 HA GFTYSGIRTNGATSACRRSRSSFYAEMKWLLSNTDNAAFP 546235368 QMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNKL VTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD CYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQRSLLLATGM KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN EVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTIDLA DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF GASCFILLAIVMGLVFICVKNGNMRCTICI 83 AGW82612A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shanghai/JSO VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 1/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/03 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 546235388 NTDNAAFPQMTKSYKNTRKNPALIVWGIHHSGSTAEQTK LYGSGNKLVTVGSSNYQQSFAPSPGARTQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 84 AHA11472A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER turkey/Minnesota/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG 31676/2009 PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 2009/12/08 HA GSGGIDKESMGFTYSGIRTNGETSACRRSGSSFYAEMKWL 557478625 LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITNKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 85 AHA11483A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER turkey/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG Minnesota/14135- PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 2/2009 GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL 2009/08/07 HA LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT 557478644 KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 86 AHA11500A/ TQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVE Zhejiang/DTI VVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQC D-ZJU10/2013 DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI 2013/10/14 HA DKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT 557478676 DNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY GSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHWL MLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDA NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIVMGLVFICVKN 87 AHA57050A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER turkey/Minnesota/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG 14659/2009 PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 2009/08/12 HA GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL 558484427 LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH NCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 88 AHA57072A/ MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER turkey/Minnesota/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG 18421/2009 PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 2009/09/09 HA GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL 558484465 LSNSNDAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 89 AHD25003A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Guangdong/0 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2/20132013/10/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 568260567 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNM 90 AHF20528A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Hong VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Kong/470129/20 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 132013/11/30  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 570933555 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 91 AHF20568A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shanghai/CN VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 02/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/02 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 570933626 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQR SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 92 AHH25185A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Guangdong/0 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 4/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/16 HA GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 576106234 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 93 AHJ57411A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shanghai/PD- VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 01/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/17 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 585478041 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVSSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCKGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 94 AHJ57418A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shanghai/PD- VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 02/2014 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2014/01/17 HA GIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSN 585478256 TDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY GSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWL MLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQVDA NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFELID NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 95 AHK10800A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shanghai/01/2 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 0142014/01/03 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 587681014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 96 AHM24224A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Beijing/3/201 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 32013/04/16 QCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES HA 594704802 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 97 AHN96472A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shanghai/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP PD-CN- QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 02/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/01/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 602701641 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 98 AHZ39686A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Anhui/DEWH VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 72-01/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013//HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 632807036 NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 99 AHZ39710A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Anhui/DEWH VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 72-03/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013//HA GGIDKEAMGFTYSGIRTDGATSACRRSGSSFYAEMKWLLS 632807076 NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 100 AHZ39746A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Anhui/DEWH VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 72-06/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013//HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 632807136 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGERPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 101 AHZ41929A/ MNTQILVFALVAIIPINADKICLGHHAVSNGTKVNTLTERG mallard/Sweden/ VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP 1621/2002 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2002/12/12 HA GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 632810949 NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI 102 AHZ42537A/ MNTQILAFIACMLVGAKGDKICLGHHAVANGTKVNTLTE mallard/ RGIEVVNATETVETANIKKLCTQGKRPTDLGQCGLLGTLI Minnesota/AI09- GPPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQIL 3770/2009 RGSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKW 2009/09/12 HA LLSNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQ 632811964 TKLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTELWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 103 AHZ42549A/ MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTE ruddy KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG turnstone/ PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG Delaware/A100- SGGIDKESMGFTYSGIRTNGATSACRRLGSSSFYAEMKWL 1538/2000 LSNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT 2000/05/20 HA KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF 632811984 HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI 104 AID70634A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shanghai/Mix VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 1/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/03 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 660304650 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE LIDNEFNEVEKQISNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 105 AIN76383A/ MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER Zhejiang/LSO GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP 1/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/08 HA GGIDKEAMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLLS 684694637 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 106 AIU46619A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Zhejiang/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP DTID- QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES ZJU06/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/12/ HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 699978931 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVEV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 107 AIU47013A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Suzhou/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 040201H/201 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 32013/04/ HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 699979673 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV 108 AJJ90490A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 742/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/10 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755178094 SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 109 AJJ90526A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 898/2013 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2013/12/09 HA GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS 755178154 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 110 AJJ90538A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Shenzhen/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 918/2013 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/09 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755178174 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 111 AJJ90576A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1665/2013 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2013/12/12 HA GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS 755178238 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 112 AJJ90588A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2110/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/13 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755178258 SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 113 AJJ90661A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2912/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/18 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755178380 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 114 AJJ90673A/ MNTQILVFALTAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 3049/2013 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/18 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755178400 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 115 AJJ90795A/ MNTQILVFALIAIIPTNADKICLGHHAVPNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 3281/2013 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/18 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755178604 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 116 AJJ90891A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 3520/2013 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/19 HA SNTDNAAFPQMTKSYKNTRKXPALIVWGIHHSVSTAEQT 755178764 KLYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDF HWLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQ VDANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 117 AJJ90951A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 3544/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/19 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755178864 SNTDNAAFPQMTKSYRNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 118 AJJ91035A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 3780/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/19 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755179004 SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 119 AJJ91155A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 4037/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/19 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755179204 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 120 AJJ92005A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 801/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/09 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755180629 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 121 AJJ94254A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1374/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755184382 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 122 AJJ94606A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 191/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/02/20 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755184968 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDMILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 123 AJJ96552A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP 12206/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/16 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188219 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 124 AJJ96684A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKINTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 13207/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188439 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 125 AJJ96732A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 13223/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188519 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 126 AJK00354A/ MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER duck/Zhejiang/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP LS02/2014 PQCDQFLEFSADLIVERREGSDVCYPGKFVNEEALRQILRE 2014/01/12 HA SGGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 755194469 SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK LYGSGNKLITVGSSNYQQSFVPSPGARPLVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQ QFELIDHEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF HKCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSS GYKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 127 AJJ91264A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 4129/2013 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/19 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755179386 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLMEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 128 AJJ91314A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shaoxing/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2417/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/10/20 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755179470 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 129 AJJ91402A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Huzhou/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 4045/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/10/24 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755179618 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KEVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 130 AJJ91476A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Huzhou/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 4076/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2013/10/24 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755179743 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 131 AJJ91725A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shaoxing/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 5201/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/10/28 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755180161 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 132 AJJ91885A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP4/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/16 HA GGIDKEAMGFTYSGIRANGVTSACRRSGSSFYAEMKWLL 755180429 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 133 AJJ91909A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP2 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 6/2014 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2014/01/20 HA GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS 755180469 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDGCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 134 AJJ91945A/ MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP3 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 8/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/22 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755180529 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIGGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 135 AJJ91957A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP4 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 4/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/23 HA GGIDKEAMGFTYSGIRANGTTSACRRSGSSFYAEMKWLLS 755180549 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 136 AJJ91969A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP4 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 8/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/23 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755180569 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 137 AJJ91993A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 4119/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/19 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755180609 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLLGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFTLLAIVMGLVFICVKNGNMRCTICI 138 AJJ92031A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 4064/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/19 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755180672 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVESSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 139 AJJ92967A/ MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER silkie GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP chicken/Jiangxi/ PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 9469/2014 GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 2014/02/16 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755182232 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 140 AJJ93027A/ MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER chicken/Jiangxi/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP 9558/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES 2014/02/16 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755182332 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 141 AJJ93051A/ MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER chicken/Jiangxi/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP 10573/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/18 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755182372 NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 142 AJJ93845A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 157/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755183695 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 143 AJJ93857A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 169/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/02/20 HA GGIDKEAMGFTYSGIRTNGATSACMRSGSSFYAEMKWLL 755183715 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 144 AJJ93869A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP 173/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755183735 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 145 AJJ93881A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP 189/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755183755 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPKYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 146 AJJ93907A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 449/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755183799 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 147 AJJ93931A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 536/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/02/20 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755183839 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISKLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 148 AJJ93943A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 568/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 755183859 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 149 AJJ93979A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP chicken/Dongguan/ PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 656/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755183919 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF GLIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 150 AJJ94134A/ MNTQILVLALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1051/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755184182 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVXLSXGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 151 AJJ94158A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1075/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755184222 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 152 AJJ94182A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1177/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACKRSGSSFYAEMKWLLS 755184262 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSIAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 153 AJJ94194A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1264/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755184282 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQQ FELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI 154 AJJ94206A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1268/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/21 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755184302 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISDLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 155 AJJ94344A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNSTETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 1451/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL 755184532 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRTVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 156 AJJ94356A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1456/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755184552 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 157 AJJ94396A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1494/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755184618 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 158 AJJ94754A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 748/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 755185215 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSNAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 159 AJJ94838A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 835/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755185356 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFGFGASCFILLAIVMGLVFICVKNGNMRCTICI 160 AJJ94862A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 843/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIEKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755185396 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 161 AJJ94886A/ MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 851/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755185436 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 162 AJJ94910A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 874/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/20 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755185476 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 163 AJJ94959A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 967/2014 GGIDKEAMGFTYSGIRANGATSACXRSGSSFYAEMKWLL 2014/02/21 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755185558 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 164 AJJ95048A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 1009/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755185708 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 165 AJJ95171A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1314/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755185913 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFNFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 166 AJJ95227A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1382/2014 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2014/02/21 HA GIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 755186006 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 167 AJJ95251A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1401/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755186046 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 168 AJJ95346A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1548/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755186206 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 169 AJJ95382A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 1690/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/02/21 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755186266 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 170 AJJ95464A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 138/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/19 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755186404 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI 171 AJJ95572A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Dongguan/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 1100/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/21 HA GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 755186584 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 172 AJJ95584A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1519/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755186604 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI 173 AJJ95596A/ MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP5 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 8/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/25 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755186624 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 174 AJJ95620A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP7 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 5/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/15 HA GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS 755186664 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAVVMGLVFICVKNGNMRCTICI 175 AJJ95632A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP6 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/05 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755186684 NTDNATFPQMTKSYKNTRKSPALIIWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 176 AJJ96720A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTTIPRICSKGKKTVDLGQCGLLGTITGPP 13220/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188499 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 177 AJJ96817A/ MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER chicken/Jiangxi/ GVEVVNATEIVERTNIPRICSKGKKTVDLGQCGLLGTITGP 9513/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/16 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755188661 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 178 AJJ96841A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG Shenzhen/SP1 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 39/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/04/02 HA GGIDKEAMGFTYSGIRTNGATSTCRRSGSSFYAEMKWLLS 755188701 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRACFLRGKSMGIQSGVQ VDADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVERQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 179 AJJ96889A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTXIPRICSKGKKTVDLGQCGLLGTITGPP 13496/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/11 HA GGIDKXAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 755188781 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSXGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 180 AJJ96901A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 13502/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/11 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188801 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSXGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 181 AJJ96925A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13513/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/11 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755188841 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHTVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDLH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 182 AJJ97267A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13252/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755189411 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 183 AJJ97291A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13493/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755189451 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 184 AJJ97331A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13512/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755189517 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 185 AJJ97373A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13521/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755189587 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPXRASFLRGKSXGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 186 AJJ97443A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTTIPRICSKGKRTVDLGQCGLLGTITGPP 13530/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755189702 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 187 AJJ97582A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 14023/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/13 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755189933 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 188 AJJ97697A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 14517/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/20 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190125 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCDGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 189 AJJ97709A/ MNTQILVFALIAIIPANADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 14518/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/20 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755190145 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGNCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 190 AJJ97745A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 14554/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/20 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190205 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELMDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 191 AJJ97757A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shantou/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2537/2014  QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/04/16 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190225 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 192 AJJ97841A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG duck/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 15044/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/27 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190365 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVRLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 193 AJJ97899A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 15524/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/05/05 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190462 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFMCVKNGNMRCTICI 194 AJJ97925A/ MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Shantou/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2050/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/03/25 HA NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL 755190506 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 195 AJJ97973A/ MNTQILVFALISIIPTNADKICLGHHAVSNGTKVNTLTERG chicken/Shantou/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 4325/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/07/01 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755190586 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 196 AJJ97998A/ MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER chicken/Shantou/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP 4816/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/07/22 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190628 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELVDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI

TABLE 14 H10 Hemagglutinin Amino Acid Sequences SEQ ID Accession No/ NO Strain/Protein Amino Acid Sequence 197 AAM19228 ACVLVEAKGDKICLGHHAVVNGTKVNTLTEKGIEVVNAT A/turkey/ ETVETANIGKICTQGKRPTDLGQCGLLGTLIGPPQCDQFLE Minnesota/ FESDLIIERREGNDVCYPGKFTNEESLRQILRGSGGIDKESM 38429/ GFTYSGIITNGATSACRRSGSSFYAEMKWLLSNSDNAAFP 1988 1988// QMTKSYRNPRNKPALIVWGIHHSGSTTEQTKLYGSGNKLI HA 20335017 TVESSKYQQSFTPSPGARPQVNGESGRIDFHWMLLDPNDT VTFTFNGAFIAPDRASFFKGESLGVQSDVPLDSSCGGDCFH SGGTIVSSLPFQNINPRTVGKCPRYVKQPSLLLATGMRNVP ENPKTRGLFGAIAGFIEKDGGSHYG 198 AAY46211 MNTQILVFALVAIIPINADKICLGHHAVSNGTKVNTLTERG A/mallard/ VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP Sweden/91/ PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2002 2002// GGIDKETMGFTYSGIRTNGAPSACRRSGSSFYAEMKWLLS HA 66394828 NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI 199 ABI84694 MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE A/turkey/ KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG Minnesota/1/ PPQCDQFLEFESDLIIERREGNDVCYPGKETNEESLRQILRG 1988 1988/07/13  SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 115278573 SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN QHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHAQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 200 ABS89409 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/blue-winged GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP teal/Ohio/566/ PQCDQFLEFDTDLIIERREGTDVCYPGKFTNEESLRQILRGS 2006 2006//  GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 155016324 NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKL YGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHW LLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDS GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGKGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD DQCMESIRNNTYDHTQYRTESLQNRIQIDPVRLSSGYKDII LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 201 ACD03594 MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTE A/ruddy KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG turnstone/DE/1538/ PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG 2000 2000// SGGIDKESMGFTYSGIRTNGATSACRRLGSSFYAEMKWLL HA 187384848 SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI 202 BAH22785 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/duck/Mongolia/ GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP 119/2008 2008// PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 223717820 GGIGKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRTVGKCPRYVKQESLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 203 CAY39406 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/Anas crecca/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Spain/1460/ PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2008 2008/01/26 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 254674376 SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LMLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFTEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 204 ACX53683 MNIQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERG A/goose/Czech VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP Republic/1848-K9/ PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE 2009 2009/02/04 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 260907763 SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 205 ACZ48625 MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE A/turkey/ KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG Minnesota/38429/ PPQCDQFLEFESDLIIERREGNDVCYPGKFTNEESLRQILRG 1988 1988// SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 269826341 SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL 206 ADC29485 STQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGNVI A/mallard/Spain/ NWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNKLY 08.00991.3/ ERVKRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTYD 2005 2005/11/  HSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFILL HA 284927336 207 ADK71137 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/blue-winged GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP teal/Guatemala/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG CIP049-01/2008 SGGIDKESMGFTYSGIRTNGATSACRRSGSSSYAEMKWLL 2008/02/07  SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTK HA 301333785 LYGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLD SGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLL LATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQHFE LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDI ILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 208 ADK71148 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/blue-winged GIEVVNXTETVETANIKKICTHGKRPTDLGQCGLLGTLIGP teal/Guatemala/ PQCDRFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRGS CIP049-02/2008 GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2008/03/05  NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKL HA 301333804 YGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFHW LLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLDS GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD DQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDII LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 209 ADN34727 MNIQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERG A/goose/Czech VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP Republic/1848- PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE T14/2009 SGGIDKETMGFTYSGIRTNGXTSACRRSGSSFYAEMKWLL 2009/02/04  SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK HA 307141869 LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 210 AEK84760 PAFIAPDRASFLRGKSMGIQSGVQVDASCEGDCYHSGGTII A/wild SNLPFQNINSRAVGKCPRYVKQESLMLATGMKNVPELPK bird/Korea/A14/ GRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQGEGTAAD 2011 2011/02/ YKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGN HA 341610308 VINWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNK LYERVRRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTY DHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFIL LAIAMGLVFICVKNGNMRCTICI 211 AEK84761 ILVFALVAIIPTNANKIGLGHHAVSNGTKVNTLTERGVEVF A/wild bird/ NATETVERTNVPRICSKGKKTVDLGQCGLRGTITGPPQCD Korea/A3/2011 QFLKFSPDLIIERQKGSDVCYPGKFVNEKPLRQILRESGGID 2011/02/ KETMGFAYNGIKTNGPPIACRKSGSSFYAKMKWLLSNTD HA 341610310 KAAFPQMTKSYKNTRRNPALIVWGIHHSGSTTKQTKLYGI GSNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN PNDTVTFSFNGAFIPPDRASFLRGKSMGIQSGVQVDASCEG DCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATG MKNVPELPKGKGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTI DLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 212 AEK84763 ILVFALVAIIPTNANKIGLGHHAVSNGTKVNTLTERGVEFF A/wild bird/ NATETVEPTNVPRICSKGKKTVDLGQCGLLGTITGPPQCD Korea/A9/2011 QFLEFSADLIIERREGSDVCYPGKFVNEKALRQILRESGGID 2011/02/ KETMGFAYSGIKTNGPPIACRKSGSSFYAKMKWLLSNTDK HA 341610314 AAFPQMTKSYKNIRRDPALIVWGIHHSGSTTKQTNLYGIG SNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNP NDTVTFIFNGAFIAPDRASFLIGKSMGIQSGVQVDASCEGD CYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATGM KNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNA QGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEF TEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID LADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIAMGLVFICVKNGNMRCTICI 213 AEK84765 LVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVV A/spot-billed NATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQCD duck/Korea/447/ QFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGID 2011 2011/04/ KETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD HA 341610318 NAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTKLYGS GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN PNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDASCE GDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLAT GMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQ NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN EFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHT IDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD CMARIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 214 AEM98291 SILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV A/wild VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC duck/Mongolia/ DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI 1-241/2008 DKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT 2008/04/  DNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKLYG HA 344196120 SGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLM LNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDAN CEGDCYHSGGSIISNLPFQNINSRAVGKCPRYVKQESLML ATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSGYKD VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI 215 AFM09439 QILAFIACMLIGAKGDKICLGHHAVANGTKVNTLTERGIE A/emperor goose/ VVNATETVETVNIKKICTQGKRPTDLGQCGLLGTLIGPPQC Alaska/44063-061/ DQFLEFDADLIIERRKGTDVCYPGKFTNEESLRQILRGSGGI 2006 2006/05/23 DKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSD HA 390535062 NAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKLYGS GNKLITVGSSKYQQSFVPSPGARPQVNGQSGRIDFHWLLL DPNDTVTFTFNGAFIAPERASFFRGESLGVQSDVPLDSGCE GDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATG MRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNE FSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID LADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQC MESIRNNTYDHTQYRTESLQNRIQINPVKLSSGYKDIILWF SFGASCFLLLAIAMGLVFICIKNGNMRCTICI 216 AFV33945 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/guinea RIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP fowl/Nebraska/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG 17096-1/2011 SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/04/05  SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT HA 409676820 KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 217 AFV33947 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/goose/Nebraska/ GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP 17097-4/2011 PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG 2011/04/05 SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 409676827 SNSDNAAFPQMTKSYRNPRNKPALIVWGVHHSASATEQT KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 218 AFX85260 MNTQILAFIACMLIGINGDKICLGHHAVANGTKVNTLTER A/ruddy GIEVVNATETVETANIKRICTQGKRPIDLGQCGLLGTLIGPP turnstone/ QCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRGS Delaware Bay/ GGIDKESMGFTYSGIRTNGATSACIRLGSSFYAEMKWLLS 220/1995 NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQTK 1995/05/21  LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH HA 423514912 WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGRCPRYVKQTSL LLATGMKNVPENPKTRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQF ELIDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 219 AGE08098 MNTQILTLIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/northern GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP shoverl/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG Mississippi/ SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 110S145/ SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTK 2011 2011/01/08 LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH HA 444344488 WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHNGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 220 AGI60301 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Hangzhou/1/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013 2013/03/24 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 475662454 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGISGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 221 AGI60292 MNTQILVFALIAIIPANADKICLGHHAVSNGTKVNTLTERG A/Shanghai/4664T/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013 2013/03/05 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 476403560 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCHHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 222 AGJ72861 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ GEVVNATETVERTNIPRICSKGKKTVDLGQGGPRGTITGPP Zhejiang/DTID- QCDQFLEFSADLIMERREGSDVCYPGKFVNEEALRQILRES ZJU01/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/04/  NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL HA 479280294 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 223 AGJ73503 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Nanjing/1/2013 VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 2013/03/28 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 479285761  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 224 BAN16711 MNTQVLVFALMAIIPTNADKICLGHHAVSNGTKVNTLTER A/duck/Gunma/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG 466/2011 2011// PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE HA 482661571 SGGIDKETMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLL SNTDNAAFPQMTKSYKNTRRDPALIAWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDDTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 225 AGK84857 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Hangzhou/2/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013 2013/04/01 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 485649824 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQITKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 226 AGL44438 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shanghai/02/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013 2013/03/05 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 496493389 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 227 AGL33692 GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR A/Shanghai/4655T/ LIEKTNQQFELIDNEFTEVEKQIGNVINWTRDSITEVWSYN 2013 2013/02/26 AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG HA 491874175 TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID PVKLSSGYKDVILWFSFGASCFILLAIAMGLVFICVKNGN MRCTICI 228 AGL33693 GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR A/Shanghai/4659T/ LIEKTNQQFELIDNEFNEVEKQIGNVINWTRDSITEVWSYN 2013 2013/02/27 AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG HA 491874186 TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID PVKLSSGYKDVILWFSFGASCFILLAIVMGLVFICVKNGN MRCTICI 229 AGL95088 VFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN A/Taiwan/S02076/ ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF 2013 2013/04/22 LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE HA 501485301 AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIVMGLVFICVKNGNMR 230 AGL95098 LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN A/Taiwan/T02081/ ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF 2013 2013/04/22 LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE HA 501485319 AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIVMGLVFICVKNGNMRCT 231 AGM53883 GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ A/Shanghai/5083T/ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM 2013 2013/04/20 ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH HA 507593986 KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCT 232 AGM53884 AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE A/Shanghai/5180T/ FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID 2013 2013/04/23 LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC HA 507593988 MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIVMGLVFICVKNGNMRCTICI 233 AGM53885 QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID A/Shanghai/5240T/ NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH 2013 2013/04/25 TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD HA 507593990 DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIVMGLVFICVKNGNMRCT 234 AGM53886 NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN A/Shanghai/4842T/ EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI 2013 2013/04/13 DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD HA 507593992 CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL WFSFGASCFILLAIVMGLVFICVKNGNMRCT 235 AGM53887 NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN A/Shanghai/4701T/ EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI 2013 2013/04/06 DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD HA 507593994 CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL WFSFGASCFILLAIVMGLVFICVKNGNMRCTIC 236 AGN69462 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Wuxi/2/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/03/31 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 511105778 GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 237 AGN69474 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Wuxi/1/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/03/31 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 511105798 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLINGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 238 AGO51387 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Jiangsu/2/2013 VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 2013/04/20 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 514390990 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRXEAMXBXIQIDPVKLSSGY KDVXJWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 239 BAN59726 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/duck/Mongolia/ GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP 147/2008 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2008/08/29 HA GGIGKETMGFTYSGIRTNGATSACRRSRSSFYAEMKWLLS 519661951 NTDNAAFPQMTRSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRTVGKCPRYVKQESLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 240 BAN59727 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/duck/Mongolia/ GVEVVNATETVERINVPRICSKGKRTVDLGQCGLLGTITG 129/2010 2010// PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE HA 519661954 SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 241 AGQ80952 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/duck/Jiangxi/ GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP 3096/2009 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2009// HA GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 523788794 NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRAVGKCPRYVKQESL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 242 AGQ80989 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/duck/Jiangxi/ GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP 3257/2009 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2009// HA GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 523788868 NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGXSNYQQSFVPSPGARPQVNGQSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHNGGTIISNLPFQNINSRAVGKCPRYVKQESL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 243 AGQ81043 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Rizhao/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 515/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013// HA GGIDKEEMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 523788976 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 244 AGR33894 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Rizhao/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 719b/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013// HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 524845213 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDRSKYREEAMQNRXXXXXXXXXXX XKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 245 AGR49399 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP SD001/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2013/05/03 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 525338528 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 246 AGR49495 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP Shanghai/S1358/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/04/03 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 525338689 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIKNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 247 AGR49506 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Shanghai/S1410/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/04/03 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 525338708 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 248 AGR49554 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Zhejiang/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES SD033/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/04/11 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 525338789 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVRRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 249 AGR49566 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/duck/Anhui/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP SC702/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/16 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 525338809 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 250 AGR49722 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/homing VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP pigeon/Jiangsu/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES SD184/2013 GGIDKEAMGFTYSEIRTNGATSACRRSGSSFYAEMKWLLS 2013/04/20 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 525339071 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 251 AGR49734 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/pigeon/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP S1069/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/02 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 525339091 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTITFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 252 AGR49770 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/wild VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP pigeon/Jiangsu/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES SD001/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/04/17 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 525339151 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 253 AGY41893 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Huizhou/01/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2013 2013/08/08 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 552049496 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 254 AGY42258 FALVAIIPINADKICLGHHAVSNGTKVNTLTERGVEVVNA A/mallard/Sweden/ TETVERTNVPRICSRGKRTVDLGQCGLLGTIXGPPQCDQFL 91/2002 EFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKET 2002/12/12 HA MGFTYSGIRTNGAXSACRRSGSSFYAEMKWLLSNTDNAA 552052155 FPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKLYGSGNK LITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNPND TVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDANCEGDC YHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLLATGMK NVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG EGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTE VEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTIDLA DSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDCMA SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF GASCFILLAIAMGLVFMCVKNGNMRCTICI 255 AHA11441 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/guinea GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP fowl/Nebraska/ PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG 17096/2011 SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 2011/04/10 HA SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT 557478572 KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 256 AHA11452 MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE A/turkey/ RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG Minnesota/ PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR 32710/2011 GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL 2011/07/12  LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ HA 557478591 TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FEMIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 257 AHA11461 MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE A/turkey/ RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG Minnesota/ PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR 31900/2011 GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL 2011/07/05 LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ HA 557478606 TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 258 AHK10585 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Guangdong/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES G1/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/05/05 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL HA 587680636 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 259 AGG53366 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/wild duck/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Korea/CSM42-34/ PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2011 2011/03/ SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 459252887 SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 260 AGG53377 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/wild duck/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Korea/CSM42-1/ PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2011 2011/03/ SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 459252925 SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT 261 AGG53399 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/wild duck/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Korea/MHC39-26/ PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2011 2011/03/ SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 459253005 SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 262 AGG53432 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/wild duck/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Korea/MHC35-41/ PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2011 2011/03/ SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 459253136 SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT 263 AGG53476 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/wild duck/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Korea/SH19-27/ PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2010 2010/12/ SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 459253257 SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI 264 AGG53487 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/wild duck/ GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG Korea/SH19-50/ PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE 2010 2010/01/ SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL HA 459253278 SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 265 AGG53520 QILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV A/wild duck/ VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC Korea/SH20-27/ DQLLEFSADLIIERREGTDVCYPGKFVNEEALRQILRESGGI 2008 2008/12/ EKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD HA 459253409 NAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKLYGS GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLML NPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANC EGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLA TGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH TIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSGYKDVI LWFSFGASCFILLAIAMGLVFICVKNGNMR 266 AGL43637 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Taiwan/1/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013// HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 496297389 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGPSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIINNLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 267 AGL97639 IACMLVGAKGDKICLGHHAVANGTKVNTLTERGIEVVNA A/mallard/ TETVETANIKKLCTQGKRPTDLGQCGLLGTLIGPPQCDQFL Minnesota/AI09- EFDADLIIERREGTDVCYPGKFTNEESLRQILRGSGGIDKES 3770/2009 MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSDNAA 2009/09/12  FPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKLYGSGNK HA 505555371 LITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHWLLLDPN DTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDSGCEGDC FHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATGMRN VPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG EGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNEFSEI EQQIGNVINWTRDSMTELWSYNAELLVAMENQHTIDLAD SEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQCMESI RNNTYDHTQYRTESLQNRIQIDPVKLS 268 AGO02477 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Xuzhou/1/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/04/25 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 512403688 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 269 AGR84942 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Suzhou/5/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/04/12 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304561 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 270 AGR84954 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Nanjing/6/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/04/11 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304594 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNRNMRCTICI 271 AGR84978 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Wuxi/4/2013 VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2013/04/07 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 526304656 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 272 AGR84990 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Wuxi/3/2013 VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013/04/07 HA QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 526304688 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 273 AGR85002 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Zhenjiang/1/ VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 2013 2013/04/07 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304708 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNKRCTICI 274 AGR85026 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Nanjing/2/2013 VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP 2013/04/05 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 526304762 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI 275 AGU02230 LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVN A/Zhejiang/ ATETVERTNIPRICSKGKRTVDLGQCGLRGTITGPPQCDQF DTID-ZJU05/  LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE 2013 2013/04/  AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA HA 532808765 AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW FSFGASCFILLAIVMGLVFICVKNGNMRCT 276 AGU02233 FALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVNAT A/Zhejiang/ ETVERTNFPRICSKGKRTVDLGQCGLRGTITGPPQCDQFLE DTID-ZJU08/2013  FSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEA 2013/04/ HA MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNAA 532808788 FPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNK LVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD CYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATGM KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN EVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTIDLA DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF GASCFILLAIVMGLVFICVKNGNMRCT 277 AGW82588 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/tree VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP sparrow/Shanghai/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 01/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/05/09 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 546235348 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTIGI 278 AGW82600 ALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVNATE A/Shanghai/ TVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQFLEF CN01/2013 SADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEAM 2013/04/11 HA GFTYSGIRTNGATSACRRSRSSFYAEMKWLLSNTDNAAFP 546235368 QMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNKL VTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD CYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQRSLLLATGM KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN EVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTIDLA DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF GASCFILLAIVMGLVFICVKNGNMRCTICI 279 AGW82612 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP JS01/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/03 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 546235388 NTDNAAFPQMTKSYKNTRKNPALIVWGIHHSGSTAEQTK LYGSGNKLVTVGSSNYQQSFAPSPGARTQVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFTEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI 280 AHA11472 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/turkey/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG Minnesota/31676/ PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 2009 2009/12/08  GSGGIDKESMGFTYSGIRTNGETSACRRSGSSFYAEMKWL HA 557478625 LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITNKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 281 AHA11483 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/turkey/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG Minnesota/ PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 14135-2/2009 GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL 2009/08/07 HA LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT 557478644 KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 282 AHA11500 TQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVE A/Zhejiang/ VVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQC DTID-ZJU10/2013  DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI 2013/10/14 HA DKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT 557478676 DNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY GSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHWL MLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDA NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIVMGLVFICVKN 283 AHA57050 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/turkey/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG Minnesota/14659/ PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 2009 2009/08/12  GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL HA 558484427 LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH NCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 284 AHA57072 MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER A/turkey/ GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG Minnesota/18421/ PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR 2009 2009/09/09  GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL HA 558484465 LSNSNDAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 285 AHD25003 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Guangdong/02/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2013 2013/10/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 568260567 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNM 286 AHF20528 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Hong VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Kong/470129/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/11/30 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 570933555 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 287 AHF20568 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP CN02/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/02 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 570933626 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQR SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 288 AHH25185 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Guangdong/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 04/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/12/16 HA GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 576106234 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 289 AHJ57411 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP PD-01/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/17 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 585478041 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVSSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCKGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 290 AHJ57418 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP PD-02/2014 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2014/01/17 HA GIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSN 585478256 TDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY GSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWL MLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQVDA NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFELID NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 291 AHK10800 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shanghai/01/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2014 2014/01/03 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES HA 587681014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 292 AHM24224 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Beijing/3/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 2013 2013/04/16 QCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES HA 594704802 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 293 AHN96472 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shanghai/PD-CN- QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 02/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/01/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 602701641 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 294 AHZ39686 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Anhui/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP DEWH72-01/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013// HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 632807036 NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 295 AHZ39710 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Anhui/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP DEWH72-03/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013// HA GGIDKEAMGFTYSGIRTDGATSACRRSGSSFYAEMKWLLS 632807076 NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 296 AHZ39746 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Anhui/  VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP DEWH72-06/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013// HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 632807136 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGERPQVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 297 AHZ41929 MNTQILVFALVAIIPINADKICLGHHAVSNGTKVNTLTERG A/mallard/Sweden/ VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP 1621/2002 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2002/12/12 HA GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 632810949 NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI 298 AHZ42537 MNTQILAFIACMLVGAKGDKICLGHHAVANGTKVNTLTE A/mallard/ RGIEVVNATETVETANIKKLCTQGKRPTDLGQCGLLGTLI Minnesota/ GPPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQIL AI09-3770/2009 RGSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKW 2009/09/12 HA LLSNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQ 632811964 TKLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ FELIDNEFSEIEQQIGNVINWTRDSMTELWSYNAELLVAM ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH KCDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGY KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI 299 AHZ42549 MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTE A/ruddy KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG turnstone/ PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG Delaware/AI00- SGGIDKESMGFTYSGIRTNGATSACRRLGSSSFYAEMKWL 1538/2000 LSNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT 2000/05/20 HA KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF 632811984 HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI 300 AID70634 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shanghai/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Mix1/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/03 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 660304650 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE LIDNEFNEVEKQISNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 301 AIN76383 MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER A/Zhejiang/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP LS01/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/08 HA GGIDKEAMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLLS 684694637 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 302 AIU46619 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Zhejiang/DTID- QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES ZJU06/2013 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2013/12/ HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 699978931 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVEV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 303 AIU47013 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Suzhou/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 040201H/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/04/ HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 699979673 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDMILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 304 AJJ90490 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shenzhen/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 742/2013 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/10 HA SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK 755178094 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 305 AJJ90526 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shenzhen/898/2013 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2013/12/09 HA GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS 755178154 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 306 AJJ90538 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Shenzhen/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 918/2013 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/09 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755178174 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 307 AJJ90576 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shenzhen/1665/ QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2013 2013/12/12 GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS HA 755178238 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 308 AJJ90588 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shenzhen/2110/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/13  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755178258 SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 309 AJJ90661 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/2912/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/18  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755178380 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 310 AJJ90673 MNTQILVFALTAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 3049/2013  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/18 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755178400 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 311 AJJ90795 MNTQILVFALIAIIPTNADKICLGHHAVPNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES Dongguan/3281/  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013 2013/12/18  SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK HA 755178604 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 312 AJJ90891 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES Dongguan/3520/  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013 2013/12/19  SNTDNAAFPQMTKSYKNTRKXPALIVWGIHHSVSTAEQT HA 755178764 KLYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDF HWLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQ VDANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 313 AJJ90951 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/3544/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/19  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755178864 SNTDNAAFPQMTKSYRNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 314 AJJ91035 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shenzhen/3780/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/19  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755179004 SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 315 AJJ91155 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/4037/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/19  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755179204 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 316 AJJ92005 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shenzhen/801/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/09  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755180629 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 317 AJJ94254 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/1374/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014 2014/02/21  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 755184382 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 318 AJJ94606 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/191/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014 2014/02/20  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 755184968 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 319 AJJ96552 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP 12206/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/16 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188219 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 320 AJJ96684 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKINTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 13207/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188439 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 321 AJJ96732 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiang VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP xi/13223/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188519 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 322 AJK00354 MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER A/duck/Zhejiang/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP LS02/2014 PQCDQFLEFSADLIVERREGSDVCYPGKFVNEEALRQILRE 2014/01/12 HA SGGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 755194469 SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK LYGSGNKLITVGSSNYQQSFVPSPGARPLVNGQSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQ QFELIDHEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF HKCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSS GYKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 323 AJJ91264 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 4129/2013  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2013/12/19 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755179386 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLMEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 324 AJJ91314 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Shaoxing/2417/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/10/20  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 755179470 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHW LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 325 AJJ91402 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Huzhou/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 4045/2013  QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013/10/24 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755179618 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KEVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 326 AJJ91476 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Huzhou/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 4076/2013 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2013/10/24 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755179743 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 327 AJJ91725 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Shaoxing/5201/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/10/28  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS HA 755180161 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 328 AJJ91885 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP4/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/16 HA GGIDKEAMGFTYSGIRANGVTSACRRSGSSFYAEMKWLL 755180429 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 329 AJJ91909 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP26/2014 QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 2014/01/20 HA GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS 755180469 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDGCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 330 AJJ91945 MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP38/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/22 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755180529 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIGGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 331 AJJ91957 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP SP44/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/23 HA GGIDKEAMGFTYSGIRANGTTSACRRSGSSFYAEMKWLLS 755180549 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 332 AJJ91969 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP48/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/23 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755180569 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 333 AJJ91993 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/4119/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/19  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755180609 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLLGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFTLLAIVMGLVFICVKNGNMRCTICI 334 AJJ92031 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/4064/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2013 2013/12/19  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL HA 755180672 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVESSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 335 AJJ92967 MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER A/silkie GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP chicken/Jiangxi/ PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 9469/2014 GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 2014/02/16 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755182232 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 336 AJJ93027 MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER A/chicken/Jiangxi/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP 9558/2014  PQCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES 2014/02/16 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755182332 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 337 AJJ93051 MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER A/chicken/Jiangxi/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP 10573/2014 PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/18 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755182372 NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 338 AJJ93845 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 157/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755183695 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 339 AJJ93857 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 169/2014 GGIDKEAMGFTYSGIRTNGATSACMRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK 755183715 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 340 AJJ93869 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP Dongguan/ PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 173/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755183735 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 341 AJJ93881 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP Dongguan/ PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 189/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755183755 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPKYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 342 AJJ93907 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 449/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755183799 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 343 AJJ93931 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 536/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/20 HA NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL 755183839 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISKLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 344 AJJ93943 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 568/2014 GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 2014/02/20 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755183859 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 345 AJJ93979 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP chicken/Dongguan/ PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 656/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755183919 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF GLIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 346 AJJ94134 MNTQILVLALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 1051/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL 755184182 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVXLSXGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 347 AJJ94158 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1075/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755184222 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 348 AJJ94182 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1177/2014 GGIDKEAMGFTYSGIRTNGATSACKRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSIAEQTKL 755184262 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 349 AJJ94194 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1264/2014  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755184282 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQQ FELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI 350 AJJ94206 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1268/2014  GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/21 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755184302 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISDLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 351 AJJ94344 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNSTETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 1451/2014  GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL 755184532 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRTVGKCPRYVKQRSL LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 352 AJJ94356 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1456/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755184552 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 353 AJJ94396 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1494/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/21 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755184618 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 354 AJJ94754 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 748/2014 GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 2014/02/20 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSNAEQTK 755185215 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 355 AJJ94838 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 835/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK 755185356 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFGFGASCFILLAIVMGLVFICVKNGNMRCTICI 356 AJJ94862 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 843/2014 GGIEKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/20 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755185396 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 357 AJJ94886 MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 851/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755185436 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 358 AJJ94910 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 874/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/20 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK 755185476 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 359 AJJ94959 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 967/2014 GGIDKEAMGFTYSGIRANGATSACXRSGSSFYAEMKWLL 2014/02/21 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755185558 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 360 AJJ95048 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1009/2014 GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 2014/02/21 HA SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK 755185708 LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 361 AJJ95171 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1314/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755185913 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFNFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 362 AJJ95227 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG 1382/2014 GIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755186006 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 363 AJJ95251 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1401/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755186046 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 364 AJJ95346 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1548/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755186206 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 365 AJJ95382 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 1690/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL 755186266 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 366 AJJ95464 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP Shenzhen/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 138/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/19 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755186404 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI 367 AJJ95572 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1100/2014 GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755186584 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 368 AJJ95584 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP chicken/Dongguan/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 1519/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/02/21 HA NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL 755186604 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI 369 AJJ95596 MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP58/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/01/25 HA GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL 755186624 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 370 AJJ95620 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP75/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/15 HA GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS 755186664 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAVVMGLVFICVKNGNMRCTICI 371 AJJ95632 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP62/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/05 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755186684 NTDNATFPQMTKSYKNTRKSPALIIWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 372 AJJ96720 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTTIPRICSKGKKTVDLGQCGLLGTITGPP 13220/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188499 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 373 AJJ96817 MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER A/chicken/Jiangxi/ GVEVVNATEIVERTNIPRICSKGKKTVDLGQCGLLGTITGP 9513/2014  PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/02/16 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755188661 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 374 AJJ96841 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/Shenzhen/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP SP139/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/04/02 HA GGIDKEAMGFTYSGIRTNGATSTCRRSGSSFYAEMKWLLS 755188701 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRACFLRGKSMGIQSGVQ VDADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVERQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 375 AJJ96889 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTXIPRICSKGKKTVDLGQCGLLGTITGPP 13496/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/11 HA GGIDKXAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL 755188781 SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSXGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 376 AJJ96901 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 13502/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/11 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755188801 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSXGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 377 AJJ96925 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13513/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/11 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755188841 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHTVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDLH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 378 AJJ97267 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13252/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/03/30 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755189411 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 379 AJJ97291 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13493/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755189451 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 380 AJJ97331 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13512/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755189517 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 381 AJJ97373 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 13521/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755189587 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPXRASFLRGKSXGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 382 AJJ97443 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTTIPRICSKGKRTVDLGQCGLLGTITGPP 13530/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/06 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755189702 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 383 AJJ97582 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 14023/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/13 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755189933 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 384 AJJ97697 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 14517/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/20 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190125 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCDGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 385 AJJ97709 MNTQILVFALIAIIPANADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 14518/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/20 HA GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL 755190145 SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGNCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 386 AJJ97745 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 14554/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/20 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190205 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELMDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 387 AJJ97757 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Shantou/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 2537/2014  QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/04/16 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190225 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 388 AJJ97841 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/duck/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 15044/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/04/27 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190365 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVRLSSGY KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 389 AJJ97899 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Jiangxi/ VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP 15524/2014 QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/05/05 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190462 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY KDVILWFSFGASCFILLAIVMGLVFMCVKNGNMRCTICI 390 AJJ97925 MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG A/silkie VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP chicken/Shantou/ QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2050/2014 GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 2014/03/25 HA NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL 755190506 YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 391 AJJ97973 MNTQILVFALISIIPTNADKICLGHHAVSNGTKVNTLTERG A/chicken/Shantou/ VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP 4325/2014  QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS 2014/07/01 HA GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS 755190586 NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI 392 AJJ97998 MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER A/chicken/Shantou/ GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP 4816/2014  PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES 2014/07/22 HA GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS 755190628 NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF ELVDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI

TABLE 15 Examples of Wild type Hemagglutinin Antigens SEQ ID Protein/ NO Strain Nucleic Acid Sequence 393 H1 AGCAAAAGCAGGGGAAAATAAAAACAACCAAAATGAAGGCAAACCTACTGGTCCTG TTATGTGCACTTGCAGCTGCAGATGCAGACACAATATGTATAGGCTACCATGCGAA CAATTCAACCGACACTGTTGACACAGTGCTCGAGAAGAATGTGACAGTGACACACT CTGTTAACCTGCTCGAAGACAGCCACAACGGAAAACTATGTAGATTAAAAGGAATA GCCCCACTACAATTGGGGAAATGTAACATCGCCGGATGGCTCTTGGGAAACCCAGA ATGCGACCCACTGCTTCCAGTGAGATCATGGTCCTACATTGTAGAAACACCAAACT CTGAGAATGGAATATGTTATCCAGGAGATTTCATCGACTATGAGGAGCTGAGGGAG CAATTGAGCTCAGTGTCATCATTCGAAAGATTCGAAATATTTCCCAAAGAAAGCTC ATGGCCCAACCACAACACAACCAAAGGAGTAACGGCAGCATGCTCCCATGCGGGGA AAAGCAGTTTTTACAGAAATTTGCTATGGCTGACGGAGAAGGAGGGCTCATACCCA AAGCTGAAAAATTCTTATGTGAACAAGAAAGGGAAAGAAGTCCTTGTACTGTGGGG TATTCATCACCCGTCTAACAGTAAGGATCAACAGAATATCTATCAGAATGAAAATG CTTATGTCTCTGTAGTGACTTCAAATTATAACAGGAGATTTACCCCGGAAATAGCA GAAAGACCCAAAGTAAGAGATCAAGCTGGGAGGATGAACTATTACTGGACCTTGCT AAAACCCGGAGACACAATAATATTTGAGGCAAATGGAAATCTAATAGCACCAAGGT ATGCTTTCGCACTGAGTAGAGGCTTTGGGTCCGGCATCATCACCTCAAACGCATCA ATGCATGAGTGTAACACGAAGTGTCAAACACCCCTGGGAGCTATAAACAGCAGTCT CCCTTTCCAGAATATACACCCAGTCACAATAGGAGAGTGCCCAAAATACGTCAGGA GTGCCAAATTGAGGATGGTTACAGGACTAAGGAACATTCCGTCCATTCAATCCAGA GGTCTATTTGGAGCCATTGCCGGTTTTATTGAAGGGGGATGGACTGGAATGATAGA TGGATGGTACGGTTATCATCATCAGAATGAACAGGGATCAGGCTATGCAGCGGATC AAAAAAGCACACAAAATGCCATTAACGGGATTACAAACAAGGTGAACTCTGTTATC GAGAAAATGAACATTCAATTCACAGCTGTGGGTAAAGAATTCAACAAATTAGAAAA AAGGATGGAAAATTTAAATAAAAAAGTTGATGATGGATTTCTGGACATTTGGACAT ATAATGCAGAATTGTTAGTTCTACTGGAAAATGAAAGGACTCTGGATTTCCATGAC TCAAATGTGAAGAATCTGTATGAGAAAGTAAAAAGCCAATTAAAGAATAATGCCAA AGAAATCGGAAATGGATGTTTTGAGTTCTACCACAAGTGTGACAATGAATGCATGG AAAGTGTAAGAAATGGGACTTATGATTATCCCAAATATTCAGAAGAGTCAAAGTTG AACAGGGAAAAGGTAGATGGAGTGAAATTGGAATCAATGGGGATCTATCAGATTCT GGCGATCTACTCAACTGTCGCCAGTTCACTGGTGCTTTTGGTCTCCCTGGGGGCAA TCAGTTTCTGGATGTGTTCTAATGGATCTTTGCAGTGCAGAATATGCATCTGAGAT TAGAATTTCAGAAATATGAGGAAAAACACCCTTGTTTCTACT 394 H7 AGCGAAAGCAGGGGATACAAAATGAACACTCAAATCCTGGTATTCGCTCTGATTGC GATCATTCCAACAAATGCAGACAAAATCTGCCTCGGACATCATGCCGTGTCAAACG GAACCAAAGTAAACACATTAACTGAAAGAGGAGTGGAAGTCGTCAATGCAACTGAA ACAGTGGAACGAACAAACATCCCCAGGATCTGCTCAAAAGGGAAAAGGACAGTTGA CCTCGGTCAATGTGGACTCCTGGGGACAATCACTGGACCACCTCAATGTGACCAAT TCCTAGAATTTTCAGCCGATTTAATTATTGAGAGGCGAGAAGGAAGTGATGTCTGT TATCCTGGGAAATTCGTGAATGAAGAAGCTCTGAGGCAAATTCTCAGAGAATCAGG CGGAATTGACAAGGAAGCAATGGGATTCACATACAGTGGAATAAGAACTAATGGAG CAACCAGTGCATGTAGGAGATCAGGATCTTCATTCTATGCAGAAATGAAATGGCTC CTGTCAAACACAGATGATGCTGCATTCCCGCAGATGACTAAGTCATATAAAAATAC AAGAAAAAGCCCAGCTCTAATAGTATGGGGGATCCATCATTCCGTATCAACTGCAG AGCAAACCAAGCTATATGGGAGTGGAAACAAACTGGTGACAGTTGGGAGTTCTAAT TATCAACAATCTTTTGTACCGAGTCCAGGAGCGAGACCACAAGTTAATGGTCTATC TGGAAGAATTGACTTTCATTGGCTAATGCTAAATCCCAATGATACAGTCACTTTCA GTTTCAATGGGGCTTTCATAGCTCCAGACCGTGCAAGCTTCCTGAGAGGAAAATCT ATGGGAATCCAGAGTGGAGTACAGGTTGATGCCAATTGTGAAGGGGACTGCTATCA TAGTGGAGGGACAATAATAAGTAACTTGCCATTTCAGAACATAGATAGCAGGGCAG TTGGAAAATGTCCGAGATATGTTAAGCAAAGGAGTCTGCTGCTAGCAACAGGGATG AAGAATGTTCCTGAGATTCCAAAGGGAAGAGGCCTATTTGGTGCTATAGCGGGTTT CATTGAAAATGGATGGGAAGGCCTAATTGATGGTTGGTATGGTTTCAGACACCAGA ATGCACAGGGAGAGGGAACTGCTGCAGATTACAAAAGCACTCAATCGGCAATTGAT CAAATAACAGGAAAATTAAACCGGCTTATAGAAAAAACCAACCAACAATTTGAGTT GATAGACAATGAATTCAATGAGGTAGAGAAGCAAATCGGTAATGTGATAAATTGGA CCAGAGATTCTATAACAGAAGTGTGGTCATACAATGCTGAACTCTTGGTAGCAATG GAGAACCAGCATACAATTGATCTGGCTGATTCAGAAATGGACAAACTGTACGAACG AGTGAAAAGACAGCTGAGAGAGAATGCTGAAGAAGATGGCACTGGTTGCTTTGAAA TATTTCACAAGTGTGATGATGACTGTATGGCCAGTATTAGAAATAACACCTATGAT CACAGCAAATACAGGGAAGAGGCAATGCAAAATAGAATACAGATTGACCCAGTCAA ACTAAGCAGCGGCTACAAAGATGTGATACTTTGGTTTAGCTTCGGGGCATCATGTT TCATACTTCTAGCCATTGTAATGGGCCTTGTCTTCATATGTGTAAAGAATGGAAAC ATGCGGTGCACTATTTGTATATAAGTTTGGAAAAAAACACCCTTGTTTCTAC 395  H10 ATGTACAAAATAGTAGTGATAATCGCGCTCCTTGGAGCTGTGAAAGGTCTTGATAA AATCTGTCTAGGACATCATGCAGTGGCTAATGGGACCATCGTAAAGACTCTCACAA ACGAACAGGAAGAGGTAACCAACGCTACTGAAACAGTGGAGAGTACAGGCATAAAC AGATTATGTATGAAAGGAAGAAAACATAAAGACCTGGGCAACTGCCATCCAATAGG GATGCTAATAGGGACTCCAGCTTGTGATCTGCACCTTACAGGGATGTGGGACACTC TCATTGAACGAGAGAATGCTATTGCTTACTGCTACCCTGGAGCTACTGTAAATGTA GAAGCACTAAGGCAGAAGATAATGGAGAGTGGAGGGATCAACAAGATAAGCACTGG CTTCACTTATGGATCTTCCATAAACTCGGCCGGGACCACTAGAGCGTGCATGAGGA ATGGAGGGAATAGCTTTTATGCAGAGCTTAAGTGGCTGGTATCAAAGAGCAAAGGA CAAAACTTCCCTCAGACCACGAACACTTACAGAAATACAGACACGGCTGAACACCT CATAATGTGGGGAATTCATCACCCTTCTAGCACTCAAGAGAAGAATGATCTATATG GAACACAATCACTGTCCATATCAGTCGGGAGTTCCACTTACCGGAACAATTTTGTT CCGGTTGTTGGAGCAAGACCTCAGGTCAATGGACAAAGTGGCAGAATTGATTTTCA CTGGACACTAGTACAGCCAGGTGACAACATCACCTTCTCACACAATGGGGGCCTGA TAGCACCGAGCCGAGTTAGCAAATTAATTGGGAGGGGATTGGGAATCCAATCAGAC GCACCAATAGACAATAATTGTGAGTCCAAATGTTTTTGGAGAGGGGGTTCTATAAA TACAAGGCTTCCCTTTCAAAATTTGTCACCAAGAACAGTGGGTCAGTGTCCTAAAT ATGTGAACAGAAGAAGCTTGATGCTTGCAACAGGAATGAGAAACGTACCAGAACTA ATACAAGGGAGAGGTCTATTTGGTGCAATAGCAGGGTTTTTAGAGAATGGGTGGGA AGGAATGGTAGATGGCTGGTATGGTTTCAGACATCAAAATGCTCAGGGCACAGGCC AGGCCGCTGATTACAAGAGTACTCAGGCAGCTATTGATCAAATCACTGGGAAACTG AATAGACTTGTTGAAAAAACCAATACTGAGTTCGAGTCAATAGAATCTGAGTTCAG TGAGATCGAACACCAAATCGGTAACGTCATCAATTGGACTAAGGATTCAATAACCG ACATTTGGACTTATCAGGCTGAGCTGTTGGTGGCAATGGAGAACCAGCATACAATC GACATGGCTGACTCAGAGATGTTGAATCTATATGAAAGAGTGAGGAAACAACTAAG GCAGAATGCAGAAGAAGATGGGAAAGGATGTTTTGAGATATATCATGCTTGTGATG ATTCATGCATGGAGAGCATAAGAAACAACACCTATGACCATTCACAGTACAGAGAG GAAGCTCTTTTGAACAGATTGAATATCAACCCAGTGACACTCTCTTCTGGATATAA AGACATCATTCTCTGGTTTAGCTTCGGGGCATCATGTTTTGTTCTTCTAGCCGTTG TCATGGGTCTTTTCTTTTTCTGTCTGAAGAATGGAAACATGCGATGCACAATCTGT ATTTAG

TABLE 16 Codon Optimized Sequences Encoding H1 Hemagglutinin Seq ID No. Nucleotide sequence 396 ATGAAGGCAAACCTCTTAGTCCTTCTCTGCGCACTGGCCGCTGCCGACGCAGATACCATA TGTATCGGTTATCACGCCAATAACTCTACCGATACAGTCGATACGGTGCTTGAGAAAAAC GTCACCGTGACTCATAGCGTGAACCTGCTCGAGGACTCCCATAACGGTAAGCTATGCCGA CTAAAGGGCATCGCCCCCCTGCAGCTGGGGAAATGCAACATCGCTGGCTGGTTGTTAGGT AATCCCGAATGCGATCCACTGCTGCCCGTGAGATCCTGGTCTTACATCGTCGAAACCCCT AACTCTGAAAATGGCATCTGCTATCCGGGAGACTTTATTGACTATGAGGAGCTCCGAGAA CAGCTGAGCTCAGTATCCAGCTTTGAACGCTTCGAAATTTTTCCAAAGGAATCCAGCTGG CCAAACCATAACACGAATGGCGTCACAGCCGCATGCAGCCACGAGGGAAAGAGCAGCTTT TATAGGAACCTTCTGTGGTTGACGGAAAAAGAGGGAAGTTATCCCAAACTTAAAAACAGC TATGTGAATAAAAAGGGCAAGGAGGTCTTGGTACTTTGGGGAATCCATCACCCTCCAAAC AGTAAGGAACAACAAAATCTGTACCAGAATGAAAATGCATACGTGTCCGTGGTTACATCT AATTACAACCGACGGTTTACTCCCGAGATCGCCGAGCGACCGAAAGTTCGCGACCAGGCC GGGAGGATGAACTATTATTGGACGTTGCTGAAACCCGGTGACACAATTATCTTTGAGGCA AATGGTAATCTTATCGCCCCGATGTACGCATTCGCACTGTCGCGCGGATTTGGCAGTGGG ATTATAACCAGTAACGCATCTATGCATGAATGCAACACAAAGTGCCAGACTCCTTTAGGC GCTATAAACTCTTCTTTGCCCTATCAGAATATACACCCAGTGACCATCGGCGAGTGTCCA AAGTACGTACGCAGCGCCAAGCTCCGAATGGTTACAGGCCTCAGAAATAACCCCAGTATC CAGAGCCGCGGCTTATTCGGGGCGATCGCTGGATTTATTGAGGGGGGCTGGACGGGAATG ATAGATGGGTGGTACGGCTACCATCATCAGAATGAGCAGGGTAGCGGCTATGCGGCCGAC CAGAAAAGCACCCAGAACGCTATCAACGGTATAACCAATAAAGTGAACACTGTGATCGAA AAAATGAACATACAGTTCACTGCCGTGGGAAAGGAATTCAACAAACTGGAAAAAAGGATG GAAAATCTTAACAAAAAAGTGGATGACGGGTTTTTGGACATTTGGACATACAATGCCGAA CTGCTGGTTCTGCTGGAGAACGAAAGGACACTGGACTTTCACGATTCCAACGTCAAGAAT CTCTATGAAAAAGTGAAGTCCCAATTGAAAAACAACGCCAAGGAGATCGGTAATGGGTGC TTTGAGTTCTATCACAAGTGTGACAACGAGTGCATGGAGAGCGTTAGGAACGGCACATAC GATTACCCAAAATATTCTGAGGAGTCTAAGTTGAACAGAGAGAAGGTCGATGGCGTTAAA CTGGAAAGCATGGGAATTTACCAGATCCTTGCCATCTACTCCACCGTGGCCTCCTCCCTT GTGCTGCTGGTGTCGCTGGGGGCCATCTCCTTTTGGATGTGCTCCAATGGTTCACTGCAA TGTCGAATCTGCATC 397 ATGAAGGCTAACCTCCTAGTGCTGCTCTGTGCCTTGGCGGCTGCGGATGCTGACACCATT TGCATTGGGTACCACGCCAATAATTCAACCGATACTGTCGACACCGTGTTGGAGAAGAAT GTGACCGTGACTCATTCCGTGAACCTTCTTGAAGATTCGCACAACGGGAAGCTGTGTCGA CTCAAAGGCATCGCGCCTCTACAGTTGGGCAAATGTAACATCGCTGGGTGGCTGCTCGGG AACCCAGAATGTGATCCTTTGCTGCCAGTGAGATCGTGGTCATACATTGTGGAGACCCCC AATTCAGAGAACGGGATATGCTACCCAGGTGACTTTATCGATTATGAGGAACTTCGGGAA CAACTGTCTTCAGTGTCGTCATTTGAGCGTTTCGAGATCTTTCCCAAAGAGTCCTCGTGG CCAAACCACAACACTAACGGCGTTACTGCCGCCTGCTCACATGAAGGAAAGAGCTCATTC TACAGAAACCTGTTGTGGCTCACCGAGAAGGAGGGGAGTTATCCCAAGTTGAAAAACAGT TATGTTAACAAGAAGGGCAAAGAAGTGTTAGTCCTGTGGGGAATCCACCACCCACCGAAT TCTAAAGAGCAGCAGAATCTATATCAGAACGAGAACGCCTATGTGTCAGTTGTAACTTCA AATTACAACCGCAGGTTTACTCCTGAAATCGCGGAGCGCCCGAAAGTGCGTGATCAGGCT GGACGTATGAATTACTACTGGACTTTGCTAAAACCTGGCGACACCATCATTTTCGAAGCT AACGGCAATCTCATTGCGCCGATGTACGCCTTTGCTCTCTCTAGGGGGTTCGGGTCTGGG ATCATTACCAGCAATGCTTCCATGCACGAGTGTAATACAAAGTGCCAGACTCCCCTCGGC GCGATTAATAGCTCGCTCCCCTACCAAAACATACACCCAGTGACAATTGGCGAGTGCCCT AAATATGTGCGCTCTGCTAAGTTACGTATGGTGACGGGCCTAAGAAACAACCCCTCAATT CAGAGCAGGGGGCTGTTCGGAGCTATTGCAGGTTTCATCGAAGGGGGCTGGACAGGGATG ATCGACGGCTGGTATGGGTATCACCACCAGAACGAACAGGGATCCGGCTATGCTGCCGAT CAGAAATCAACACAAAATGCAATCAATGGCATCACTAACAAAGTGAATACCGTAATTGAG AAGATGAACATACAGTTTACCGCTGTCGGTAAAGAATTCAACAAGCTGGAGAAACGGATG GAGAATCTGAACAAGAAAGTCGATGATGGCTTCTTGGATATCTGGACCTATAATGCTGAG TTACTTGTGCTCTTGGAAAACGAGCGTACTCTCGACTTTCATGATTCAAATGTCAAGAAT CTGTATGAAAAGGTAAAGTCCCAGCTAAAAAACAATGCCAAGGAGATCGGGAATGGCTGC TTTGAATTCTACCACAAATGCGATAATGAGTGCATGGAGTCGGTGAGGAACGGAACCTAC GATTACCCAAAATATAGCGAGGAATCAAAACTGAACAGAGAGAAGGTGGATGGTGTGAAG CTGGAATCCATGGGTATCTACCAGATCCTCGCCATCTATTCAACTGTGGCTAGTTCCCTG GTGCTGCTCGTGAGCCTTGGTGCAATCTCCTTCTGGATGTGTTCCAACGGGTCATTGCAG TGTAGGATCTGCATA 398 ATGAAGGCTAACTTGCTGGTCTTGCTTTGCGCGCTGGCCGCTGCTGACGCCGACACCATC TGTATTGGGTATCATGCTAACAACTCCACGGATACCGTGGATACAGTGTTGGAAAAAAAT GTTACAGTTACTCATTCGGTGAACCTGCTGGAGGACTCTCACAATGGGAAGCTGTGCAGG CTCAAAGGTATCGCTCCGCTCCAACTAGGCAAATGTAATATTGCCGGCTGGCTGTTAGGA AACCCAGAGTGTGACCCTCTCTTACCCGTGAGATCTTGGTCCTACATCGTCGAGACCCCC AACAGCGAAAACGGAATTTGTTATCCCGGAGACTTCATAGATTATGAGGAGCTGCGCGAA CAGCTCTCTTCTGTTAGCTCTTTTGAGCGTTTTGAGATCTTTCCTAAAGAGAGTTCATGG CCCAACCACAATACCAACGGAGTGACAGCCGCATGCTCCCATGAAGGGAAGTCTAGCTTC TATAGAAATCTTCTGTGGCTGACTGAAAAAGAAGGATCTTACCCCAAGTTGAAGAATTCT TATGTGAACAAAAAGGGCAAAGAGGTGTTGGTACTCTGGGGCATTCATCACCCACCTAAT TCAAAGGAGCAGCAAAACCTTTATCAAAACGAGAATGCCTATGTTAGCGTCGTCACTTCT AATTATAACCGGAGATTCACCCCGGAGATAGCGGAACGCCCCAAGGTTCGGGATCAGGCT GGCCGCATGAATTACTACTGGACCCTCCTAAAACCTGGCGACACCATAATCTTCGAAGCA AATGGCAACCTGATCGCACCTATGTACGCCTTTGCGCTGTCTAGGGGATTCGGCTCGGGC ATTATTACCAGTAATGCCTCAATGCACGAGTGTAATACAAAATGCCAGACCCCTCTGGGA GCCATTAATTCTAGTCTGCCTTATCAGAATATTCATCCTGTGACCATTGGCGAATGTCCG AAATATGTTAGATCCGCAAAGCTGCGAATGGTTACCGGACTTCGCAACAACCCCTCTATA CAAAGCCGCGGACTCTTTGGAGCAATCGCTGGCTTCATTGAGGGTGGCTGGACGGGCATG ATCGATGGGTGGTACGGATACCATCATCAGAACGAGCAGGGAAGCGGATATGCCGCAGAC CAAAAATCTACTCAGAACGCTATTAACGGAATTACCAACAAAGTCAACACAGTTATCGAG AAAATGAATATTCAGTTCACCGCAGTTGGTAAGGAATTTAACAAACTGGAGAAACGAATG GAGAACTTGAACAAGAAGGTCGACGATGGCTTCTTAGACATCTGGACATATAATGCCGAA CTGTTGGTCCTCCTGGAGAACGAGAGAACCTTGGACTTTCACGACTCTAACGTGAAGAAT CTTTACGAGAAGGTGAAGTCCCAACTGAAGAATAATGCAAAAGAGATCGGAAACGGCTGT TTTGAGTTCTACCACAAGTGCGACAATGAGTGCATGGAGAGCGTGCGGAATGGGACATAT GATTATCCCAAGTATAGTGAAGAAAGCAAGCTGAATCGAGAAAAGGTTGACGGAGTGAAG CTGGAGAGCATGGGGATCTACCAGATCTTAGCAATTTATAGCACAGTGGCTTCTTCCCTT GTGTTGCTGGTCTCGCTGGGAGCTATCAGCTTTTGGATGTGCAGCAACGGAAGTCTGCAG TGCCGCATTTGCATT 399 ATGAAAGCCAACCTGTTGGTGCTGTTATGCGCGCTGGCAGCCGCAGATGCTGATACTATC TGTATCGGATACCATGCCAATAACAGCACCGATACCGTGGATACTGTGTTAGAGAAGAAT GTGACAGTGACGCATTCAGTAAACCTCCTCGAGGACAGTCATAATGGAAAACTGTGTAGG CTCAAGGGTATAGCTCCGCTGCAGCTGGGCAAGTGTAACATCGCTGGGTGGCTGCTGGGC AACCCTGAATGCGATCCCCTGTTGCCCGTTCGGAGTTGGTCTTACATCGTGGAGACCCCA AACTCTGAGAACGGAATTTGTTACCCCGGTGACTTTATCGATTACGAGGAATTGCGGGAG CAGCTTAGCTCAGTGTCTTCATTTGAACGGTTTGAAATCTTTCCCAAGGAAAGCAGCTGG CCCAATCATAATACTAACGGCGTGACTGCCGCTTGTTCCCACGAAGGCAAGAGCTCCTTC TACAGAAATCTGCTTTGGTTGACAGAGAAAGAGGGCAGCTATCCAAAGCTGAAGAACAGT TATGTGAATAAGAAGGGCAAGGAGGTCCTGGTTCTTTGGGGGATCCATCATCCCCCTAAT AGTAAGGAGCAGCAGAACTTATACCAGAATGAGAATGCCTACGTCAGCGTTGTCACCTCA AACTATAACCGGCGATTTACACCCGAAATTGCCGAACGTCCCAAGGTCCGCGACCAAGCC GGGCGTATGAACTACTATTGGACACTTCTGAAACCTGGGGACACAATAATTTTCGAAGCC AACGGTAACTTAATCGCTCCCATGTACGCTTTCGCTCTCAGCAGGGGCTTCGGCAGCGGC ATTATCACTTCCAATGCGTCCATGCATGAATGTAATACGAAGTGCCAGACCCCTCTCGGT GCCATAAACTCTTCTCTCCCCTACCAGAACATTCACCCTGTCACCATAGGAGAATGCCCA AAGTATGTCCGGTCGGCAAAGTTGAGGATGGTTACGGGCCTGCGTAACAACCCTTCTATA CAGTCTAGGGGCCTGTTCGGAGCAATCGCCGGCTTCATCGAAGGAGGCTGGACTGGGATG ATCGATGGCTGGTACGGCTATCATCACCAGAATGAGCAGGGCTCAGGTTATGCAGCCGAT CAGAAGTCCACACAGAACGCTATTAACGGGATAACGAACAAGGTGAACACCGTCATTGAA AAGATGAACATTCAGTTTACAGCCGTTGGAAAAGAGTTCAACAAACTGGAAAAGCGGATG GAGAACCTGAACAAAAAGGTGGACGATGGATTTCTGGATATTTGGACATATAACGCCGAG CTGCTGGTACTCCTTGAGAACGAGCGTACGCTTGACTTTCATGACAGTAACGTGAAGAAT CTGTACGAGAAGGTCAAAAGCCAGCTGAAGAACAATGCCAAAGAAATTGGGAACGGGTGT TTCGAATTCTACCACAAGTGTGACAATGAATGCATGGAGAGTGTTCGGAACGGAACCTAC GACTATCCTAAATATTCTGAGGAGTCCAAGCTGAATCGGGAAAAGGTTGACGGGGTGAAA CTGGAGAGTATGGGAATCTACCAGATCCTGGCTATTTACTCCACAGTCGCTTCCTCTCTC GTCTTGTTGGTGTCCCTTGGTGCCATCTCATTTTGGATGTGTTCTAATGGTTCTCTTCAG TGCCGAATCTGTATA 400 ATGAAAGCTAACCTTCTCGTATTGCTCTGCGCTTTGGCTGCAGCCGATGCCGATACGATT TGCATCGGATACCACGCAAATAACAGCACTGACACTGTGGACACGGTACTGGAAAAGAAT GTTACCGTGACACACTCCGTCAACCTGCTCGAGGACTCCCACAACGGAAAGTTGTGTAGG CTTAAAGGTATCGCCCCTCTACAGTTAGGGAAGTGCAACATCGCAGGGTGGTTGTTAGGA AACCCCGAATGTGACCCACTCCTGCCTGTGCGCTCTTGGAGCTATATTGTGGAAACCCCG AATAGCGAAAACGGAATTTGTTACCCTGGCGACTTTATCGATTATGAAGAGCTCCGAGAG CAACTGAGCAGCGTGTCCAGCTTTGAGCGATTTGAAATATTCCCCAAAGAGAGTTCCTGG CCCAACCATAACACTAACGGAGTGACCGCTGCATGTTCGCACGAAGGCAAATCGAGTTTT TACCGGAACCTGCTTTGGCTCACCGAGAAGGAAGGAAGTTATCCCAAACTCAAAAATTCA TACGTGAATAAAAAGGGTAAGGAGGTGCTGGTGCTGTGGGGAATCCACCATCCTCCAAAC AGCAAGGAACAACAGAATCTCTACCAGAATGAGAACGCCTATGTGAGCGTGGTAACCTCC AACTACAATCGGCGGTTCACTCCTGAGATCGCCGAGCGCCCGAAGGTCCGGGATCAAGCA GGTCGAATGAACTACTACTGGACCCTGCTGAAGCCAGGTGATACTATCATTTTCGAGGCT AATGGAAACCTGATTGCGCCTATGTACGCTTTCGCCCTGTCTAGGGGGTTTGGGTCCGGT ATCATCACGTCTAACGCTTCAATGCATGAATGCAACACGAAGTGTCAGACCCCGCTTGGC GCCATAAACAGCTCCCTCCCCTACCAGAACATTCACCCCGTCACCATAGGCGAGTGTCCC AAGTACGTGCGGTCAGCCAAGTTGCGGATGGTAACGGGCCTCCGGAATAATCCAAGTATA CAATCCCGAGGACTTTTCGGGGCAATCGCGGGCTTCATTGAGGGCGGATGGACCGGCATG ATTGATGGATGGTACGGTTACCACCACCAGAACGAGCAGGGCAGTGGATATGCCGCTGAC CAGAAGAGCACTCAGAACGCAATTAATGGCATCACCAATAAGGTGAACACCGTCATTGAG AAGATGAACATCCAGTTTACGGCAGTAGGCAAGGAGTTTAACAAGCTGGAGAAACGTATG GAAAACCTGAATAAGAAAGTGGACGACGGGTTTTTGGATATTTGGACATATAACGCCGAA CTCCTCGTGCTGCTCGAGAATGAAAGAACATTAGACTTTCACGATAGTAACGTGAAAAAC CTGTATGAAAAGGTCAAATCCCAGCTAAAGAACAACGCCAAAGAGATCGGCAATGGCTGT TTTGAGTTTTACCACAAGTGTGATAATGAATGCATGGAAAGTGTTCGGAACGGAACCTAC GATTATCCAAAATACTCGGAGGAGTCCAAACTGAATAGAGAGAAGGTGGACGGCGTCAAA CTAGAGAGTATGGGTATCTATCAGATACTTGCGATCTACTCAACCGTCGCCAGCTCCTTA GTACTTCTCGTCAGCCTCGGTGCTATCTCCTTTTGGATGTGTAGTAACGGCAGTCTGCAG TGTCGGATATGCATC 401 ATGAAGGCTAACCTGTTGGTGCTCCTATGTGCCCTGGCCGCTGCAGATGCTGACACAATC TGCATTGGGTATCATGCAAACAACTCCACCGACACTGTTGACACAGTTTTGGAAAAGAAC GTGACAGTCACTCACAGCGTAAACCTCCTGGAAGACTCACACAATGGGAAGTTATGTCGG CTGAAGGGCATAGCCCCATTGCAACTGGGCAAGTGCAATATAGCGGGGTGGCTTCTCGGC AACCCGGAATGCGACCCCCTGTTGCCCGTACGCAGCTGGAGTTACATTGTGGAGACGCCC AATTCCGAGAATGGCATCTGTTACCCGGGCGATTTCATAGATTACGAAGAACTGCGGGAG CAGCTCTCCTCCGTTTCCTCGTTCGAACGGTTCGAGATTTTCCCTAAAGAATCATCATGG CCTAATCACAATACAAATGGCGTGACGGCCGCATGCTCACACGAGGGCAAGTCCAGCTTT TACAGAAATCTCCTGTGGCTGACGGAGAAGGAAGGAAGCTACCCTAAGCTTAAGAATAGC TATGTAAACAAAAAGGGGAAGGAGGTGCTGGTTCTCTGGGGGATTCATCATCCGCCAAAT AGTAAGGAACAGCAGAACCTTTACCAGAATGAGAATGCATACGTCTCTGTGGTCACGTCT AACTACAATCGGCGCTTCACACCCGAGATCGCTGAACGGCCCAAAGTCCGGGACCAAGCC GGACGAATGAATTACTACTGGACCCTTTTGAAGCCCGGCGATACCATTATCTTCGAAGCG AACGGGAACCTGATAGCTCCCATGTACGCCTTTGCTCTCAGTAGGGGATTCGGCTCCGGC ATTATTACCTCTAATGCTTCTATGCACGAGTGCAACACAAAATGTCAGACTCCGCTCGGT GCCATCAACAGTTCGTTGCCATACCAGAATATACACCCCGTCACTATCGGGGAATGTCCT AAATACGTGAGGAGCGCCAAACTCAGGATGGTCACTGGACTCAGGAATAATCCAAGCATC CAGTCGAGGGGCTTATTCGGAGCAATTGCTGGCTTCATCGAAGGCGGGTGGACTGGCATG ATCGATGGATGGTATGGGTACCACCACCAGAACGAACAAGGTAGCGGATATGCCGCTGAC CAGAAATCAACACAAAACGCCATCAACGGTATTACCAACAAGGTTAACACTGTTATTGAG AAGATGAATATCCAATTTACCGCCGTAGGGAAGGAGTTTAATAAGTTGGAGAAACGTATG GAGAATCTGAACAAGAAAGTTGACGACGGATTTCTGGACATCTGGACCTACAACGCCGAG CTGTTAGTGCTGTTGGAAAATGAGAGAACCCTTGACTTCCATGATAGCAACGTGAAAAAC CTATATGAAAAGGTCAAGTCCCAGCTGAAGAACAATGCAAAGGAAATAGGCAATGGCTGC TTCGAGTTTTATCATAAATGCGACAACGAATGTATGGAAAGCGTCCGAAACGGCACTTAT GACTATCCCAAATATAGCGAAGAGTCAAAGCTGAATCGGGAAAAGGTGGACGGGGTCAAG CTCGAGTCAATGGGGATCTACCAGATTCTTGCAATCTATTCCACAGTGGCGTCTTCCCTC GTGCTGCTGGTTAGTCTCGGCGCCATATCATTTTGGATGTGCAGCAATGGCTCCCTGCAG TGTCGGATCTGTATC 402 ATGAAGGCGAACTTGCTGGTCCTGTTGTGCGCTTTAGCTGCTGCGGATGCCGATACAATC TGTATCGGGTATCACGCAAACAACAGTACAGATACCGTGGATACAGTTCTCGAGAAGAAT GTCACTGTTACGCACAGTGTAAACCTGCTGGAGGACAGTCACAATGGGAAGCTGTGCCGG CTAAAGGGCATTGCGCCACTACAGCTCGGCAAGTGCAATATTGCGGGGTGGTTATTGGGT AACCCCGAATGCGACCCACTATTGCCAGTGCGCTCTTGGTCGTACATCGTCGAAACCCCC AATTCAGAAAATGGCATTTGCTACCCAGGGGATTTTATAGACTACGAAGAGTTACGAGAA CAATTAAGTAGTGTTTCTTCCTTTGAGCGATTCGAGATTTTCCCCAAGGAGAGTTCTTGG CCCAACCATAACACAAATGGAGTGACTGCCGCATGCTCACACGAGGGCAAATCATCCTTT TATAGAAACCTGCTTTGGCTGACTGAAAAGGAGGGGAGTTACCCGAAGCTTAAAAACTCC TATGTGAACAAGAAGGGCAAGGAAGTGCTGGTCCTGTGGGGGATCCACCACCCACCCAAC TCCAAAGAGCAACAGAACCTCTACCAGAACGAGAATGCGTATGTGAGCGTGGTGACAAGT AACTATAATCGAAGGTTCACTCCCGAGATAGCAGAGCGTCCAAAAGTGCGAGATCAAGCC GGCCGAATGAACTACTATTGGACCTTACTGAAACCCGGCGATACCATCATATTCGAAGCT AACGGCAATCTCATAGCTCCTATGTACGCTTTCGCTTTGAGTAGAGGTTTCGGATCTGGA ATTATAACATCTAATGCATCAATGCACGAGTGCAATACTAAATGCCAGACCCCTCTTGGT GCTATCAACTCTAGTTTACCCTATCAGAACATCCACCCTGTGACGATAGGAGAGTGTCCC AAGTATGTGCGCTCCGCTAAGCTTAGAATGGTCACCGGGCTTCGGAACAACCCTTCAATC CAAAGTCGAGGGCTTTTTGGCGCTATCGCTGGCTTCATCGAAGGCGGTTGGACAGGTATG ATCGATGGTTGGTACGGCTACCATCATCAGAACGAGCAGGGGTCTGGTTATGCGGCCGAC CAAAAATCTACTCAGAATGCCATCAACGGGATCACAAATAAGGTAAACACTGTGATTGAG AAGATGAACATCCAGTTTACTGCAGTGGGAAAGGAGTTTAACAAACTGGAGAAACGTATG GAAAACCTAAACAAAAAAGTGGACGACGGATTCTTAGACATTTGGACATACAACGCCGAG CTGCTCGTGCTGCTTGAGAATGAGCGGACACTCGACTTCCACGACAGCAACGTGAAGAAC CTATACGAAAAGGTCAAGAGCCAGCTCAAGAATAACGCGAAGGAGATTGGAAACGGCTGC TTCGAGTTCTACCATAAGTGCGATAACGAATGTATGGAGTCTGTTCGGAATGGCACTTAC GACTACCCAAAGTATAGCGAGGAATCTAAGCTCAACCGAGAGAAGGTGGATGGAGTGAAA TTAGAGTCAATGGGAATTTATCAGATTCTGGCCATCTACTCAACAGTTGCGAGCTCGTTA GTGCTGCTTGTCTCACTGGGCGCGATTAGTTTTTGGATGTGCAGTAATGGGTCCCTCCAG TGTCGCATCTGCATT 403 ATGAAGGCCAACTTGCTGGTGTTACTATGTGCTCTCGCCGCCGCCGATGCCGATACTATT TGCATTGGCTATCACGCCAACAATAGTACGGACACCGTGGACACTGTCCTGGAAAAAAAT GTCACCGTCACCCATTCTGTGAATCTCCTAGAGGATTCTCATAACGGCAAGCTGTGCCGG CTTAAAGGAATCGCTCCCTTGCAGCTTGGGAAGTGCAATATCGCCGGCTGGCTCCTTGGA AACCCGGAGTGTGATCCATTGCTCCCTGTCAGAAGCTGGAGCTATATCGTTGAGACCCCG AACAGTGAGAATGGCATCTGTTACCCCGGAGATTTCATTGATTACGAGGAGCTGCGCGAA CAGCTCAGCTCAGTCTCTAGTTTCGAGCGATTTGAGATCTTCCCCAAGGAGTCTAGCTGG CCAAATCATAACACCAACGGAGTGACAGCCGCCTGTAGCCATGAAGGGAAAAGCAGCTTC TACCGAAATTTGCTGTGGCTAACTGAGAAAGAGGGGAGTTATCCTAAGCTCAAAAACAGC TATGTGAACAAGAAGGGGAAAGAAGTCCTGGTGTTGTGGGGCATCCACCATCCCCCAAAT AGCAAGGAACAGCAGAACCTTTACCAGAACGAGAATGCATACGTGAGCGTCGTAACATCC AATTATAACAGACGGTTCACACCCGAGATAGCCGAACGGCCAAAAGTGAGGGACCAGGCC GGAAGGATGAATTACTATTGGACTCTCTTAAAGCCAGGCGACACCATTATATTTGAGGCA AACGGAAACTTGATTGCGCCAATGTACGCATTCGCACTGTCACGGGGATTCGGATCCGGG ATTATCACGTCCAATGCATCGATGCATGAGTGCAACACCAAGTGTCAGACCCCACTGGGA GCCATCAATTCCAGCTTGCCCTATCAGAACATTCACCCCGTGACTATAGGAGAGTGCCCT AAATATGTCCGCAGCGCCAAACTGCGAATGGTTACCGGCCTGCGCAACAATCCTTCGATC CAGTCACGGGGCCTGTTCGGGGCCATAGCTGGCTTCATTGAGGGGGGATGGACCGGTATG ATTGATGGGTGGTACGGCTACCACCATCAGAACGAGCAGGGTTCAGGCTACGCGGCTGAC CAGAAATCCACTCAGAACGCTATCAATGGCATCACAAACAAGGTCAATACTGTTATAGAA AAAATGAATATCCAATTCACTGCTGTGGGTAAAGAGTTTAACAAGCTGGAGAAAAGAATG GAAAATCTGAACAAAAAAGTGGATGACGGCTTCTTGGATATCTGGACATACAACGCTGAA CTTCTGGTGCTGTTGGAAAACGAAAGGACTCTGGATTTCCACGATTCCAACGTGAAAAAT CTCTACGAAAAAGTTAAGTCCCAACTGAAGAATAACGCGAAGGAGATCGGAAACGGATGC TTTGAGTTCTATCATAAGTGTGATAATGAGTGTATGGAATCAGTTAGAAACGGTACGTAC GATTACCCAAAATACTCCGAAGAGTCTAAGCTGAATCGCGAGAAAGTCGATGGGGTCAAA CTCGAATCCATGGGAATTTACCAGATCTTAGCTATTTACAGTACAGTGGCCAGCTCTCTT GTCTTACTGGTGTCACTTGGCGCGATTAGTTTCTGGATGTGCTCCAATGGCAGCCTCCAG TGTCGGATTTGCATA 404 ATGAAGGCCAACCTGCTTGTACTGCTATGCGCCTTGGCTGCTGCAGACGCCGACACAATT TGCATCGGCTATCATGCCAACAATTCTACAGATACAGTGGACACTGTGCTGGAGAAAAAC GTTACTGTCACTCATAGCGTTAATCTCCTCGAGGACTCTCACAATGGAAAACTCTGTCGT CTGAAAGGCATCGCGCCACTGCAGTTGGGTAAATGTAATATCGCCGGCTGGTTGTTGGGC AACCCCGAATGTGACCCCCTCCTCCCAGTGAGGTCCTGGTCTTATATCGTAGAGACACCT AATTCGGAGAATGGAATTTGTTACCCTGGCGACTTCATAGACTATGAGGAACTGAGGGAG CAGCTTTCTTCTGTGAGTTCTTTTGAAAGATTTGAGATCTTCCCTAAAGAATCATCTTGG CCCAACCATAATACCAACGGCGTTACAGCAGCCTGTTCCCACGAGGGCAAGTCGAGTTTC TACAGGAATTTGTTATGGCTGACTGAGAAAGAGGGGTCTTATCCAAAGCTGAAAAACAGC TATGTCAACAAGAAAGGCAAAGAGGTTTTGGTGCTGTGGGGAATCCATCACCCACCAAAC TCGAAGGAACAGCAAAATCTTTACCAAAACGAAAATGCATACGTATCAGTGGTTACTAGC AATTATAATCGGCGCTTTACGCCAGAGATTGCCGAAAGACCTAAGGTGAGAGACCAAGCA GGAAGGATGAATTACTACTGGACACTACTGAAACCAGGCGATACTATCATTTTTGAGGCC AACGGAAACCTGATCGCACCCATGTACGCCTTCGCACTGTCGCGGGGTTTTGGGTCTGGC ATCATCACCTCAAATGCCAGCATGCATGAGTGCAATACTAAATGCCAAACACCTTTAGGT GCCATTAATAGCTCACTCCCCTACCAGAACATCCATCCAGTAACTATCGGGGAGTGTCCC AAGTACGTGCGATCTGCAAAACTGAGGATGGTCACTGGTTTGCGCAACAATCCCTCTATC CAGTCAAGGGGCCTATTTGGCGCAATTGCGGGCTTTATCGAGGGAGGGTGGACGGGTATG ATTGACGGATGGTACGGCTACCACCACCAGAATGAACAGGGTTCGGGGTACGCGGCAGAT CAGAAGAGTACTCAGAACGCAATTAATGGTATAACTAATAAGGTCAACACCGTAATTGAA AAAATGAATATCCAATTCACAGCTGTTGGGAAAGAATTTAACAAACTGGAGAAGAGGATG GAGAATCTCAATAAGAAGGTTGATGACGGCTTTCTCGATATCTGGACTTACAATGCTGAG CTGCTAGTTCTGCTCGAGAACGAACGGACACTCGATTTTCACGATTCCAACGTTAAAAAC CTGTACGAAAAGGTCAAATCTCAGCTGAAGAATAATGCTAAGGAAATTGGTAATGGCTGT TTCGAATTTTATCATAAATGTGATAATGAGTGCATGGAAAGTGTCCGTAACGGCACCTAC GATTATCCAAAGTATAGCGAGGAAAGCAAGCTTAATCGTGAAAAAGTAGATGGCGTGAAG CTGGAAAGTATGGGCATATATCAGATCCTGGCCATATACAGTACTGTTGCCTCCAGTCTA GTTTTACTGGTATCCCTCGGAGCTATCTCATTCTGGATGTGTAGCAATGGCAGCCTTCAG TGCCGTATCTGTATA 405 ATGAAAGCTAACCTGCTAGTTCTACTTTGTGCCCTTGCCGCTGCCGACGCTGACACCATC TGCATAGGGTACCACGCTAACAACAGTACTGACACAGTGGATACCGTTCTTGAAAAGAAC GTCACCGTAACTCACTCTGTGAATTTGCTCGAGGATTCACACAATGGGAAACTCTGCAGA CTGAAAGGAATTGCTCCACTTCAGTTGGGCAAGTGTAACATCGCTGGCTGGCTGCTTGGG AATCCGGAGTGCGACCCATTGCTGCCTGTGCGCAGTTGGAGCTACATTGTGGAGACCCCC AACAGCGAGAATGGCATCTGTTATCCCGGAGATTTCATCGACTACGAGGAGCTCCGAGAA CAATTATCCTCTGTGTCTAGTTTCGAACGGTTTGAGATCTTTCCCAAAGAATCAAGCTGG CCCAACCACAACACAAACGGTGTGACAGCAGCATGCAGTCATGAGGGCAAGTCGTCCTTC TATAGGAATCTGCTGTGGCTTACTGAGAAGGAGGGTAGCTACCCGAAACTCAAGAACTCC TACGTCAATAAGAAGGGCAAAGAGGTGTTAGTCTTGTGGGGAATACACCACCCACCCAAC TCTAAAGAGCAACAAAACCTGTACCAGAACGAAAACGCCTACGTCTCCGTAGTAACCTCA AATTATAACAGACGCTTTACGCCCGAGATCGCAGAGCGCCCCAAGGTCAGGGACCAGGCA GGGAGAATGAACTACTATTGGACTTTGTTGAAGCCCGGAGACACAATTATCTTCGAGGCG AATGGCAATCTGATTGCCCCCATGTACGCTTTTGCACTGTCCCGCGGTTTTGGTTCCGGC ATCATAACTTCCAACGCATCGATGCACGAATGTAACACCAAATGTCAGACACCATTGGGC GCCATAAACTCCAGTCTCCCATATCAAAATATCCACCCAGTCACAATCGGGGAATGTCCT AAATACGTGAGGTCAGCAAAGCTTAGGATGGTCACGGGACTGCGCAACAATCCCTCAATA CAGTCCAGAGGGCTTTTCGGAGCCATAGCCGGCTTCATCGAAGGCGGCTGGACTGGGATG ATCGATGGCTGGTATGGGTATCATCACCAGAATGAGCAGGGCTCCGGCTATGCTGCCGAT CAGAAATCCACACAGAACGCTATCAATGGGATAACTAACAAAGTTAACACCGTGATTGAG AAGATGAACATACAATTTACTGCAGTGGGAAAGGAGTTCAACAAACTGGAGAAGCGGATG GAGAACTTAAATAAAAAGGTGGATGACGGCTTCCTGGACATCTGGACTTATAACGCTGAA CTGTTGGTACTGCTTGAGAATGAGCGGACCCTCGACTTTCACGACTCAAACGTGAAGAAT CTCTATGAGAAGGTAAAATCCCAGTTGAAAAACAACGCCAAGGAGATCGGGAATGGCTGC TTTGAATTTTACCACAAGTGCGACAATGAGTGTATGGAAAGTGTGCGCAACGGAACATAT GACTATCCTAAATATAGTGAAGAGTCCAAACTGAACCGTGAAAAGGTGGATGGGGTGAAA CTCGAGTCCATGGGAATCTACCAAATCCTCGCCATTTATTCAACCGTGGCAAGCAGCCTC GTGCTACTGGTCAGTCTCGGCGCGATTTCTTTCTGGATGTGCTCCAACGGGTCACTGCAG TGTCGCATATGCATC 406 ATGAAGGCGAACCTCCTTGTGCTTCTCTGCGCTCTCGCAGCTGCTGATGCAGACACGATT TGCATAGGGTATCATGCAAACAATAGTACAGACACTGTGGACACCGTGCTGGAGAAAAAC GTGACTGTCACGCACTCAGTTAATCTTTTGGAGGACTCCCATAATGGAAAACTGTGCAGA CTTAAGGGGATCGCACCCCTGCAGTTAGGCAAGTGTAATATAGCCGGGTGGCTTCTGGGG AACCCAGAATGTGACCCACTGTTACCTGTGCGAAGCTGGTCTTACATAGTGGAGACGCCA AATTCTGAGAACGGCATCTGTTACCCTGGGGACTTTATTGATTATGAGGAACTCCGGGAA CAACTCTCGAGCGTTAGCAGCTTCGAAAGGTTTGAAATTTTTCCCAAGGAATCTTCATGG CCTAACCACAACACTAACGGTGTGACGGCTGCTTGCTCACATGAGGGAAAGTCCAGTTTC TATAGGAACCTGTTGTGGCTGACTGAGAAAGAAGGCAGCTACCCAAAGCTGAAGAACTCT TACGTTAACAAAAAAGGCAAGGAAGTGTTAGTACTGTGGGGTATCCACCACCCACCAAAC AGCAAGGAGCAGCAGAACTTGTACCAGAACGAAAATGCCTACGTCAGTGTTGTCACATCA AACTACAATAGAAGATTTACGCCAGAAATTGCCGAAAGGCCAAAGGTGCGGGACCAAGCT GGGCGGATGAACTATTATTGGACCCTTCTGAAGCCGGGAGACACGATCATATTCGAAGCA AACGGGAATCTGATCGCTCCGATGTACGCCTTCGCACTCAGCCGGGGTTTTGGATCAGGG ATCATCACATCTAACGCCTCTATGCATGAATGTAACACGAAGTGCCAGACTCCTCTAGGC GCTATCAACTCTAGCTTACCCTACCAGAATATACATCCCGTCACCATCGGCGAGTGTCCT AAGTATGTGCGCAGCGCCAAACTGCGGATGGTGACTGGCCTGAGAAATAATCCGTCCATC CAGTCAAGAGGGCTGTTTGGAGCAATCGCCGGCTTCATTGAAGGGGGCTGGACAGGTATG ATTGATGGTTGGTACGGATACCACCATCAGAATGAACAGGGGAGTGGCTACGCAGCAGAT CAAAAGTCGACACAAAACGCGATAAACGGAATCACAAACAAGGTCAATACCGTGATTGAA AAGATGAATATTCAGTTCACCGCCGTCGGCAAAGAATTTAACAAGCTTGAGAAACGTATG GAAAATCTCAATAAGAAAGTTGACGACGGTTTCTTAGACATCTGGACCTATAACGCAGAA CTGCTGGTGCTACTGGAAAACGAGAGAACCCTTGATTTCCATGATAGCAACGTGAAAAAC CTTTACGAGAAAGTTAAGAGTCAGCTCAAAAACAATGCTAAAGAAATCGGAAACGGCTGC TTCGAGTTTTATCATAAGTGCGACAATGAGTGTATGGAGAGTGTTCGAAACGGGACATAT GATTACCCGAAGTATTCAGAGGAGAGCAAACTCAATCGCGAAAAAGTTGATGGTGTGAAG CTGGAATCTATGGGCATCTACCAGATACTGGCCATCTACTCAACAGTGGCAAGTTCTCTG GTATTGCTCGTTTCCCTGGGAGCTATCTCCTTCTGGATGTGTTCGAACGGCTCACTTCAG TGTAGGATTTGCATA 407 ATGAAGGCCAACCTGTTGGTTCTCTTGTGTGCTCTGGCAGCCGCAGACGCTGACACTATT TGTATCGGATACCACGCCAATAATAGTACTGACACCGTTGACACAGTACTTGAGAAGAAC GTGACAGTAACCCACTCAGTGAACCTCCTTGAGGATAGCCACAATGGAAAATTATGTAGA CTTAAGGGTATCGCTCCCCTCCAGCTGGGCAAATGTAATATTGCCGGCTGGCTACTGGGG AATCCGGAATGTGATCCTCTCCTGCCAGTCCGATCATGGAGTTATATAGTAGAAACTCCA AATAGCGAGAATGGAATTTGTTACCCCGGCGATTTTATTGACTACGAAGAGCTCCGAGAA CAGCTCAGTTCAGTGTCTTCATTCGAACGGTTTGAAATCTTCCCAAAAGAATCCTCATGG CCCAATCACAACACTAACGGGGTCACGGCAGCATGCAGCCACGAAGGGAAGTCGTCTTTC TACCGAAATCTCCTGTGGCTGACCGAGAAAGAGGGTTCGTACCCCAAGCTCAAGAATTCT TACGTTAACAAGAAGGGGAAGGAAGTACTTGTGCTGTGGGGTATACACCATCCACCTAAT TCCAAAGAGCAGCAGAACCTGTATCAAAACGAAAATGCATACGTCAGCGTGGTTACAAGT AACTACAACAGGCGCTTTACCCCAGAGATCGCCGAGAGGCCTAAGGTTCGGGATCAGGCC GGGAGAATGAACTACTATTGGACTCTCCTCAAGCCCGGTGACACAATAATCTTCGAGGCC AATGGAAATCTTATAGCACCGATGTATGCCTTCGCACTGTCACGCGGGTTTGGCTCAGGC ATTATAACATCTAACGCTAGTATGCATGAGTGCAATACCAAGTGCCAGACCCCACTGGGT GCAATCAACAGCTCCTTGCCTTACCAGAACATACACCCAGTCACTATTGGCGAGTGCCCG AAATACGTACGCTCTGCCAAGCTGCGTATGGTCACCGGACTCCGCAATAACCCCAGTATC CAAAGCCGAGGTTTGTTTGGCGCTATTGCTGGATTCATTGAAGGAGGCTGGACGGGAATG ATTGACGGGTGGTACGGCTATCATCATCAGAATGAGCAAGGGTCAGGTTACGCCGCCGAC CAGAAGAGTACACAGAATGCAATCAACGGAATAACCAATAAGGTCAACACCGTCATCGAA AAGATGAATATCCAGTTCACGGCAGTGGGAAAGGAATTCAATAAGCTAGAAAAACGCATG GAGAATCTCAACAAGAAGGTTGACGATGGGTTTCTGGATATCTGGACATACAACGCTGAG CTGCTTGTGCTGCTGGAGAACGAGAGGACACTGGACTTCCACGACTCTAATGTCAAGAAT CTTTATGAAAAAGTCAAATCCCAGCTCAAAAATAATGCAAAGGAGATCGGAAATGGCTGC TTCGAATTCTACCACAAGTGTGACAACGAGTGCATGGAGTCTGTGCGGAACGGAACCTAC GACTATCCAAAGTATTCTGAGGAATCAAAACTCAATCGAGAGAAAGTTGATGGGGTAAAA CTGGAATCTATGGGGATTTACCAGATCCTGGCCATCTACTCCACAGTGGCTAGTTCCTTG GTTCTGTTGGTGTCTCTAGGTGCGATCTCCTTCTGGATGTGTTCCAATGGGAGTCTTCAA TGTCGAATCTGCATA 408 ATGAAGGCAAATTTGCTTGTTTTACTGTGTGCTTTGGCTGCGGCTGATGCCGACACCATA TGCATCGGTTACCACGCTAATAACAGCACCGACACAGTGGATACGGTGCTGGAGAAAAAT GTGACCGTAACTCACAGTGTGAACCTGCTTGAGGACAGCCACAACGGTAAGCTCTGCCGT CTGAAAGGAATCGCCCCGCTGCAATTGGGAAAGTGCAACATTGCTGGCTGGCTCCTGGGT AATCCTGAGTGTGACCCGCTGCTGCCCGTGCGAAGCTGGTCCTACATCGTGGAGACTCCA AACTCAGAGAACGGGATCTGTTACCCTGGAGATTTTATAGACTATGAAGAGCTAAGGGAA CAATTGTCGTCTGTCAGTTCCTTTGAACGGTTCGAGATTTTCCCAAAGGAGTCCAGTTGG CCTAATCATAATACCAATGGTGTCACTGCTGCATGTAGTCACGAAGGCAAGTCCTCATTT TATCGGAATTTGCTGTGGCTGACTGAGAAGGAGGGCAGCTATCCGAAGTTGAAGAATTCA TACGTTAATAAAAAAGGTAAGGAAGTGCTTGTCCTTTGGGGCATTCATCATCCCCCTAAC AGTAAGGAACAGCAGAATCTCTACCAGAACGAGAACGCATACGTGTCCGTGGTTACTAGT AATTACAATAGGAGGTTCACACCAGAGATTGCGGAACGGCCTAAAGTCCGGGATCAGGCC GGTAGAATGAACTATTATTGGACTTTGCTGAAACCCGGAGACACAATCATATTCGAAGCT AATGGTAACCTGATTGCTCCTATGTACGCATTCGCTCTGTCCCGTGGCTTCGGCTCCGGG ATTATCACCTCTAATGCTAGCATGCACGAGTGTAACACCAAATGCCAGACCCCACTCGGG GCGATTAACAGCAGCCTCCCATACCAGAACATTCATCCCGTTACTATAGGCGAGTGCCCA AAATATGTTCGGTCTGCAAAACTGCGGATGGTGACGGGGCTGCGAAATAACCCTTCAATA CAGAGTAGGGGGCTGTTCGGAGCAATAGCTGGTTTTATTGAGGGCGGATGGACTGGCATG ATCGATGGCTGGTATGGATACCATCACCAAAACGAGCAAGGATCTGGTTATGCAGCGGAC CAGAAGTCAACTCAGAATGCCATTAACGGCATTACTAATAAAGTTAATACCGTTATTGAA AAGATGAACATTCAGTTTACCGCCGTAGGGAAGGAGTTTAACAAGCTTGAAAAGCGCATG GAGAACCTCAACAAGAAAGTGGATGATGGGTTCCTTGACATCTGGACATATAACGCCGAA TTACTAGTGCTTTTGGAAAACGAAAGAACACTGGATTTCCATGACTCCAATGTGAAGAAT TTATATGAAAAGGTCAAAAGTCAGCTCAAGAATAATGCAAAGGAAATCGGCAATGGTTGC TTCGAATTTTACCATAAGTGTGACAACGAGTGTATGGAGAGTGTAAGGAATGGGACATAC GATTACCCAAAGTATAGCGAGGAATCAAAGCTGAACAGAGAGAAAGTGGACGGCGTGAAA TTGGAGTCCATGGGGATCTACCAGATTCTGGCGATCTATAGCACCGTCGCCAGCAGCTTG GTCTTGCTGGTATCTCTCGGGGCCATTTCCTTTTGGATGTGTTCAAATGGGAGCCTCCAA TGTAGAATCTGTATC 409 ATGAAAGCCAATCTACTGGTGTTGCTCTGTGCCCTGGCTGCTGCCGATGCTGACACGATA TGTATCGGCTACCACGCAAACAACTCCACCGATACAGTTGATACCGTGCTCGAAAAGAAT GTCACCGTAACACATAGCGTGAACCTTTTGGAGGATTCGCACAACGGTAAGCTGTGTCGT TTAAAGGGCATCGCCCCTCTTCAGCTGGGAAAATGCAATATTGCGGGCTGGTTGCTCGGT AACCCCGAGTGTGACCCTCTGCTCCCCGTGCGTAGTTGGTCATATATTGTGGAGACACCC AATAGCGAGAATGGAATTTGTTACCCCGGGGACTTTATCGATTACGAAGAGCTGCGGGAA CAACTGTCTAGTGTCAGCTCGTTCGAACGCTTTGAGATTTTCCCAAAAGAGAGCTCCTGG CCCAACCATAACACTAACGGGGTGACTGCTGCCTGTTCCCATGAGGGGAAGTCTAGTTTT TACCGAAATCTGCTGTGGCTAACGGAGAAAGAGGGCTCTTATCCAAAGCTAAAGAATAGT TACGTAAACAAGAAAGGAAAAGAGGTGCTCGTTCTCTGGGGCATTCATCACCCACCAAAC TCCAAGGAGCAGCAGAATCTGTATCAGAATGAAAACGCCTACGTATCCGTGGTGACAAGC AACTACAACAGGCGATTCACGCCCGAGATCGCCGAGCGGCCTAAAGTGAGGGATCAGGCT GGCAGGATGAACTACTATTGGACGCTGCTGAAGCCAGGGGATACTATTATTTTTGAGGCG AACGGAAACTTAATTGCCCCCATGTACGCATTTGCGCTCTCCAGAGGATTCGGCTCTGGA ATCATCACGTCAAACGCTAGCATGCACGAGTGTAATACAAAGTGTCAGACCCCACTGGGG GCAATCAATAGCAGCTTACCTTACCAAAACATCCATCCAGTGACTATCGGTGAATGCCCG AAGTACGTAAGGTCCGCAAAGCTGAGAATGGTGACGGGCCTCAGAAATAACCCTAGTATA CAGAGTCGTGGCCTGTTTGGGGCCATTGCTGGATTTATCGAAGGAGGGTGGACCGGAATG ATAGACGGCTGGTATGGCTACCACCACCAGAATGAGCAGGGATCTGGGTACGCTGCTGAT CAGAAGAGCACGCAGAACGCCATTAACGGCATAACCAACAAGGTGAATACAGTCATCGAA AAAATGAACATACAGTTTACAGCAGTTGGGAAAGAATTCAACAAACTGGAGAAGAGGATG GAAAACTTGAACAAAAAAGTCGATGACGGGTTTCTCGACATCTGGACTTACAACGCCGAG CTGCTTGTGTTACTGGAGAACGAAAGGACACTCGACTTTCACGACTCTAACGTGAAGAAT CTTTATGAGAAAGTGAAAAGCCAACTGAAAAACAATGCCAAAGAAATTGGTAACGGCTGC TTCGAGTTTTACCATAAGTGTGACAACGAGTGTATGGAATCAGTCCGCAACGGTACCTAC GACTATCCAAAATACTCTGAAGAATCAAAGCTGAATAGGGAGAAGGTGGACGGCGTTAAA TTGGAGAGCATGGGCATTTATCAAATCCTTGCCATTTATTCGACAGTGGCCTCCTCTTTA GTGCTCTTAGTGTCCCTGGGCGCCATCAGTTTCTGGATGTGTAGTAACGGCTCACTCCAA TGTCGAATTTGCATT 410 ATGAAAGCGAACCTCCTGGTTTTATTGTGCGCACTTGCCGCTGCTGATGCAGACACCATC TGTATTGGGTATCACGCGAACAATTCGACCGACACGGTCGATACAGTGCTTGAGAAAAAT GTGACTGTAACACATTCCGTGAATCTCCTCGAAGACAGCCATAACGGGAAGCTTTGCAGG CTTAAGGGGATTGCACCGCTGCAGCTCGGGAAATGTAATATAGCCGGGTGGCTATTAGGG AACCCGGAGTGCGACCCTTTGCTTCCAGTGAGGTCCTGGTCATATATTGTCGAGACCCCA AATTCAGAAAACGGGATCTGTTACCCCGGCGACTTCATTGACTACGAAGAGCTGAGGGAA CAATTAAGTTCTGTCTCCTCTTTTGAACGGTTTGAGATATTCCCAAAAGAGTCCTCCTGG CCCAATCATAACACGAATGGCGTGACAGCTGCGTGTAGCCATGAAGGGAAGAGCAGTTTC TACAGGAATCTTCTTTGGTTAACAGAAAAAGAAGGTAGTTATCCGAAACTGAAAAACAGC TACGTAAATAAAAAAGGCAAGGAGGTCCTGGTGTTGTGGGGCATTCATCACCCTCCCAAT AGCAAGGAACAGCAGAATCTCTATCAGAATGAAAACGCCTATGTCAGCGTTGTTACTAGC AACTACAACCGGCGGTTTACCCCCGAAATTGCTGAGCGACCCAAAGTTCGCGATCAGGCC GGTCGGATGAATTACTACTGGACCCTTCTGAAGCCTGGCGACACCATTATTTTTGAGGCC AACGGCAACCTAATTGCCCCAATGTATGCATTCGCCCTGAGCCGAGGTTTTGGAAGTGGC ATAATCACGTCCAATGCCTCTATGCACGAATGCAACACCAAGTGCCAGACACCCCTTGGC GCTATCAACTCTTCTCTACCTTATCAGAACATCCATCCCGTTACTATTGGGGAGTGCCCC AAATACGTCCGGTCTGCTAAACTTCGGATGGTGACAGGCCTCCGCAATAATCCTTCGATT CAAAGTCGGGGCCTGTTTGGTGCAATCGCCGGGTTCATTGAGGGAGGGTGGACTGGCATG ATCGACGGTTGGTATGGGTACCACCATCAGAACGAACAAGGCAGTGGGTACGCTGCCGAT CAGAAAAGCACCCAGAATGCTATCAACGGCATTACGAACAAGGTGAACACTGTGATAGAG AAGATGAACATCCAGTTCACTGCTGTCGGTAAAGAGTTTAACAAACTTGAAAAAAGAATG GAGAACCTCAATAAAAAGGTGGACGATGGTTTCCTGGATATATGGACATATAACGCCGAA CTACTTGTGCTCTTGGAAAATGAACGGACACTGGACTTCCACGACTCTAATGTGAAAAAT TTATATGAGAAAGTGAAGTCACAGCTCAAGAATAACGCGAAGGAAATTGGCAACGGGTGT TTCGAGTTCTATCATAAGTGCGACAATGAGTGCATGGAATCAGTTCGAAATGGAACCTAT GACTATCCAAAGTACTCAGAAGAGAGTAAACTGAACCGGGAGAAAGTCGACGGAGTCAAG CTCGAATCTATGGGTATTTATCAGATTCTGGCCATCTACAGCACAGTCGCTTCTTCTCTT GTACTGCTGGTTTCTTTGGGCGCAATCTCTTTCTGGATGTGCTCAAACGGGAGCCTGCAG TGCCGGATCTGCATC 411 ATGAAGGCTAATCTGTTAGTACTTTTATGTGCACTTGCCGCAGCTGACGCGGATACGATC TGCATTGGGTACCATGCCAACAACAGTACCGACACCGTCGATACCGTTTTGGAAAAGAAT GTGACCGTGACCCACAGCGTCAACCTTCTCGAGGATAGTCACAATGGGAAACTCTGTCGG CTGAAAGGCATAGCTCCTCTGCAGCTCGGAAAATGTAACATCGCCGGCTGGTTATTGGGG AACCCCGAATGCGATCCCCTCCTCCCAGTAAGGTCTTGGTCCTATATCGTGGAAACACCT AACAGCGAGAATGGCATCTGCTACCCCGGGGACTTCATTGATTACGAAGAACTAAGAGAA CAACTGTCGAGTGTGAGTAGTTTCGAAAGATTTGAAATATTCCCTAAGGAGTCAAGTTGG CCCAATCACAACACGAACGGCGTTACGGCAGCGTGCTCCCATGAAGGGAAATCAAGCTTC TATAGAAATCTGCTCTGGCTAACAGAAAAGGAGGGCTCATACCCAAAGTTGAAGAACTCC TACGTCAATAAAAAAGGTAAGGAAGTATTGGTCCTGTGGGGGATCCATCACCCCCCAAAT TCGAAAGAGCAACAGAACCTTTATCAGAATGAGAATGCTTACGTTAGCGTAGTTACGAGC AACTATAATCGGCGATTCACACCCGAGATTGCTGAGAGACCTAAGGTGAGAGATCAGGCA GGTCGGATGAACTACTACTGGACTCTTCTAAAGCCCGGCGATACTATAATCTTTGAGGCT AACGGCAATCTGATTGCCCCTATGTATGCTTTCGCATTGTCCAGAGGTTTTGGGAGTGGG ATCATCACGAGCAATGCCAGTATGCATGAGTGTAACACTAAATGTCAGACACCCTTAGGG GCTATCAACAGTTCTCTTCCCTATCAGAATATCCACCCAGTAACCATCGGAGAATGCCCT AAATACGTCAGATCTGCAAAACTCAGGATGGTGACTGGCCTCAGAAATAACCCCAGTATA CAGAGCAGAGGTTTATTCGGGGCGATCGCTGGCTTTATAGAAGGAGGCTGGACGGGCATG ATTGACGGCTGGTATGGCTATCATCATCAGAATGAACAGGGCAGCGGTTACGCAGCCGAC CAGAAGAGCACACAAAACGCTATTAACGGAATCACCAACAAGGTGAATACAGTCATTGAA AAAATGAATATTCAATTCACTGCAGTCGGAAAGGAATTCAACAAACTGGAAAAAAGGATG GAGAATCTCAACAAAAAAGTCGACGACGGGTTCCTGGATATCTGGACATACAATGCCGAA CTCCTCGTCCTGCTCGAGAATGAGCGGACCCTTGATTTCCACGATTCCAATGTCAAGAAC CTTTACGAGAAGGTGAAATCCCAGTTAAAGAATAACGCCAAAGAGATTGGCAATGGGTGC TTCGAATTTTATCACAAGTGCGACAACGAGTGTATGGAAAGCGTCAGAAATGGCACCTAC GACTATCCTAAATATTCAGAAGAGTCTAAACTGAATAGGGAAAAAGTCGACGGCGTCAAG CTTGAGTCTATGGGGATATATCAGATTCTTGCGATTTATTCAACTGTCGCATCCTCCCTC GTTCTGCTCGTGTCCCTGGGCGCAATCTCATTCTGGATGTGCTCTAATGGTTCATTGCAG TGTCGCATCTGTATC 412 ATGAAGGCAAACCTGCTGGTTCTTCTGTGTGCATTAGCCGCGGCCGACGCCGATACAATA TGTATCGGATACCACGCAAATAACAGCACCGACACCGTTGACACAGTGCTTGAGAAAAAC GTGACCGTGACACACAGTGTGAATCTGCTAGAGGACTCCCATAACGGGAAGCTGTGCCGG TTGAAGGGAATCGCTCCGCTGCAGTTGGGCAAATGCAATATTGCTGGGTGGCTGTTAGGT AACCCTGAATGCGATCCACTCCTCCCTGTACGTTCTTGGTCGTATATAGTGGAAACTCCC AATAGCGAAAATGGTATTTGTTATCCTGGGGATTTCATAGATTACGAAGAGCTGCGCGAA CAGCTCAGCTCTGTGAGCTCTTTCGAGCGCTTCGAAATATTCCCCAAGGAGTCCAGTTGG CCCAACCACAATACCAACGGCGTTACCGCAGCCTGTAGCCACGAGGGCAAGTCCAGCTTT TACCGCAACCTCTTGTGGTTGACCGAAAAGGAGGGAAGCTATCCGAAACTCAAGAACAGC TACGTCAATAAAAAAGGCAAGGAGGTACTAGTGCTGTGGGGCATCCACCACCCTCCAAAT AGTAAAGAGCAGCAGAATCTGTATCAGAACGAAAACGCGTATGTCTCAGTTGTGACAAGC AATTACAACCGCAGGTTCACTCCGGAGATAGCTGAAAGACCCAAAGTACGGGATCAGGCT GGGCGAATGAACTACTACTGGACACTACTCAAACCAGGTGACACCATTATTTTCGAAGCA AATGGCAATTTGATCGCACCCATGTACGCATTTGCCTTGTCCCGGGGGTTCGGCTCCGGC ATTATTACGTCTAACGCATCTATGCACGAGTGCAACACGAAATGCCAGACTCCCCTGGGG GCCATAAACTCAAGCCTGCCATATCAGAACATCCACCCGGTCACCATCGGCGAGTGCCCC AAATACGTCCGCTCAGCTAAACTCAGGATGGTCACGGGCCTCAGAAATAATCCTAGCATT CAGTCTCGCGGTCTGTTTGGCGCCATCGCAGGCTTCATTGAAGGGGGCTGGACCGGAATG ATCGATGGGTGGTACGGGTATCATCACCAGAACGAGCAAGGCAGTGGCTATGCTGCCGAT CAGAAATCAACCCAGAATGCGATTAACGGAATAACTAACAAGGTGAACACCGTCATTGAG AAGATGAATATTCAGTTCACGGCCGTCGGAAAGGAGTTTAACAAGCTCGAAAAGCGCATG GAGAACCTGAACAAGAAGGTAGATGATGGCTTCCTGGACATTTGGACCTACAATGCTGAG CTCCTCGTCTTGCTGGAGAATGAACGGACTCTCGACTTCCACGATTCCAACGTTAAGAAT TTATATGAGAAAGTGAAGAGTCAACTTAAAAACAACGCGAAGGAAATCGGTAATGGCTGC TTTGAGTTCTACCATAAGTGTGATAACGAGTGTATGGAAAGCGTGCGAAATGGGACTTAT GACTACCCTAAGTATTCGGAAGAATCTAAACTGAATAGAGAGAAGGTGGATGGGGTGAAG CTCGAATCTATGGGGATTTACCAGATCTTGGCTATCTATTCGACAGTGGCTTCCAGTCTT GTCCTACTGGTGTCTCTTGGCGCCATTTCCTTCTGGATGTGCTCCAACGGATCTCTGCAG TGCCGCATCTGTATA 413 ATGAAGGCAAATTTGTTAGTCTTGTTGTGCGCTCTGGCCGCTGCAGATGCAGACACCATC TGTATCGGGTATCACGCAAATAATTCCACAGATACAGTGGACACCGTTCTCGAGAAAAAC GTCACCGTGACCCATAGCGTGAACCTTCTCGAGGACTCTCACAACGGTAAATTATGCAGG CTTAAGGGAATAGCTCCCCTGCAACTTGGTAAGTGCAATATAGCAGGATGGCTCCTGGGC AACCCAGAATGTGACCCGCTACTGCCAGTGAGGAGCTGGTCTTACATCGTCGAAACGCCT AACTCCGAAAACGGGATCTGTTATCCTGGCGATTTCATTGATTATGAAGAGTTACGGGAG CAGTTATCAAGCGTGTCGAGCTTCGAAAGGTTTGAGATCTTCCCTAAGGAGTCAAGTTGG CCGAACCACAACACGAATGGCGTCACAGCCGCATGTTCCCATGAAGGGAAGTCCTCTTTC TATCGGAATCTTTTGTGGCTAACGGAGAAGGAGGGATCCTATCCTAAGCTTAAAAACTCC TACGTAAACAAAAAGGGCAAGGAGGTCTTAGTACTGTGGGGCATACACCACCCACCTAAC TCAAAGGAGCAGCAGAACCTTTATCAGAATGAAAATGCTTACGTCTCGGTGGTGACCAGC AACTACAACAGACGCTTCACGCCGGAAATTGCCGAGAGACCAAAGGTAAGGGATCAAGCC GGTCGAATGAATTACTATTGGACCTTATTGAAACCCGGGGACACCATCATATTTGAAGCT AACGGCAATTTGATCGCTCCAATGTACGCGTTTGCCCTTTCCCGCGGGTTCGGTTCTGGG ATCATAACCTCTAACGCTTCCATGCATGAATGTAACACAAAGTGCCAGACTCCATTAGGG GCCATTAATAGCAGTTTACCTTATCAAAATATCCACCCAGTCACTATCGGAGAGTGCCCA AAATACGTGAGGAGCGCGAAATTGAGGATGGTGACAGGCCTTCGGAACAATCCCTCTATC CAGAGCAGAGGACTGTTTGGCGCAATTGCTGGGTTTATAGAGGGGGGATGGACCGGCATG ATTGACGGATGGTACGGATACCATCATCAGAATGAGCAGGGAAGTGGATATGCTGCAGAC CAAAAGTCAACTCAGAATGCTATTAATGGTATCACCAACAAGGTGAACACAGTCATAGAA AAGATGAACATCCAGTTTACCGCCGTTGGGAAGGAATTTAACAAGCTGGAAAAAAGGATG GAGAATCTCAATAAAAAGGTAGACGATGGGTTCCTTGATATTTGGACTTACAATGCTGAG CTGTTAGTCCTACTAGAAAATGAGAGAACCCTTGACTTTCACGACTCCAACGTTAAAAAC TTATACGAGAAAGTGAAATCCCAATTAAAGAATAACGCGAAAGAGATCGGCAACGGGTGT TTCGAATTCTATCACAAATGCGACAACGAATGCATGGAGTCTGTGAGGAATGGGACTTAT GATTATCCCAAGTATTCAGAGGAGTCTAAACTGAATCGAGAAAAAGTGGACGGAGTAAAG CTGGAGTCCATGGGCATATATCAAATCCTCGCCATCTATTCCACAGTCGCCTCCTCCCTT GTTTTGTTGGTTTCCCTTGGTGCGATCAGTTTTTGGATGTGCTCTAACGGGTCCCTACAG TGCCGAATTTGTATT 414 ATGAAAGCTAATCTTCTCGTGCTACTGTGCGCCTTAGCAGCTGCCGACGCTGATACCATC TGTATAGGCTATCATGCCAATAACTCCACAGACACCGTTGATACTGTGCTTGAGAAGAAT GTGACGGTAACCCACAGCGTTAATCTCCTTGAGGACAGCCATAATGGCAAACTGTGTCGG CTGAAGGGAATCGCTCCCCTACAATTGGGAAAATGCAACATTGCAGGATGGTTGTTAGGA AACCCAGAATGCGACCCTCTACTGCCAGTGCGCAGCTGGAGTTACATTGTTGAAACACCT AACAGCGAAAATGGTATTTGCTACCCTGGGGATTTCATAGATTACGAGGAGTTAAGAGAG CAGCTGTCCAGTGTGTCTTCCTTCGAAAGGTTTGAAATCTTCCCAAAGGAGTCCTCATGG CCCAACCACAACACGAATGGCGTCACAGCTGCCTGTTCACACGAGGGTAAGTCAAGTTTT TATAGGAACTTGCTTTGGTTAACCGAAAAAGAGGGAAGCTACCCAAAGCTGAAAAATAGC TACGTGAATAAAAAGGGCAAAGAGGTGCTGGTGCTATGGGGTATCCATCATCCGCCAAAC AGCAAAGAGCAGCAAAACCTGTACCAGAACGAAAATGCCTACGTGTCTGTTGTGACGAGC AACTACAACCGTAGATTTACCCCGGAAATCGCAGAGCGGCCGAAGGTGCGCGATCAGGCG GGACGTATGAATTACTATTGGACATTGCTTAAGCCCGGAGACACAATTATTTTCGAAGCT AACGGGAATCTCATTGCCCCAATGTATGCTTTCGCACTGAGCCGAGGCTTTGGGAGCGGC ATCATCACAAGTAATGCTAGCATGCATGAGTGCAATACCAAGTGTCAAACGCCTCTGGGC GCAATCAATTCCAGTTTACCATATCAGAACATTCATCCAGTCACCATCGGGGAGTGCCCT AAATATGTAAGGTCTGCTAAACTGCGGATGGTCACTGGTCTCCGCAACAATCCATCTATC CAGAGCCGGGGTTTGTTCGGAGCTATTGCTGGATTTATAGAGGGGGGCTGGACGGGGATG ATTGATGGCTGGTACGGCTATCACCATCAGAACGAACAGGGCAGCGGCTACGCTGCAGAC CAAAAAAGTACTCAGAACGCTATTAATGGCATTACCAACAAGGTTAACACTGTGATTGAG AAGATGAACATCCAGTTCACTGCGGTAGGAAAGGAATTCAACAAACTTGAGAAGCGGATG GAAAATCTCAACAAGAAGGTAGACGATGGGTTCCTAGATATATGGACCTATAATGCCGAG CTCTTGGTCTTGTTAGAAAACGAGCGGACCTTAGACTTCCATGATAGCAACGTGAAAAAC CTGTACGAGAAAGTGAAGAGCCAGTTAAAGAATAACGCTAAGGAAATCGGAAACGGGTGC TTTGAGTTCTACCATAAGTGTGACAATGAGTGTATGGAATCTGTGCGTAACGGGACCTAC GACTACCCCAAATATTCTGAGGAATCAAAACTAAATCGAGAGAAGGTAGACGGCGTGAAG TTAGAATCTATGGGTATCTATCAAATCCTGGCTATATACTCAACCGTGGCCTCATCCCTA GTTCTCCTGGTATCCCTCGGCGCCATCTCTTTCTGGATGTGCAGCAACGGCTCTCTCCAG TGTCGCATTTGCATC 415 ATGAAGGCCAATTTGCTGGTGTTGTTGTGTGCTCTGGCAGCAGCCGATGCTGACACTATC TGCATCGGCTACCATGCCAACAATAGTACCGATACTGTGGACACTGTGTTAGAGAAGAAC GTGACAGTCACTCACTCAGTAAACTTGCTGGAGGATAGCCATAATGGCAAACTCTGTCGC CTCAAGGGCATCGCCCCTCTGCAGCTGGGAAAATGCAACATTGCTGGATGGCTGCTGGGG AACCCGGAATGCGACCCGCTGCTCCCCGTGAGATCCTGGAGTTATATAGTTGAAACTCCC AACAGTGAGAACGGGATATGTTATCCTGGCGACTTCATTGACTACGAGGAGCTGCGCGAA CAGCTCTCTAGCGTATCTTCGTTTGAACGTTTCGAAATATTTCCCAAGGAATCTTCTTGG CCAAATCACAATACCAACGGAGTCACGGCGGCCTGCTCGCACGAGGGGAAGAGTTCCTTT TATCGCAACCTACTGTGGCTCACCGAGAAGGAGGGTTCCTACCCCAAGCTGAAAAACAGC TATGTGAACAAAAAAGGCAAAGAAGTCTTGGTACTGTGGGGCATTCATCACCCACCCAAC AGCAAGGAACAGCAGAACCTGTATCAAAATGAAAATGCTTACGTCTCCGTTGTGACATCA AACTACAACAGACGGTTCACCCCTGAAATTGCTGAGAGGCCTAAGGTCAGGGACCAGGCC GGGCGGATGAATTACTACTGGACACTGCTGAAGCCGGGAGACACGATTATCTTCGAAGCA AACGGCAATCTGATCGCCCCAATGTACGCGTTTGCTCTTTCTCGGGGATTTGGCTCTGGG ATCATTACCTCTAATGCATCCATGCACGAATGCAACACCAAATGTCAGACCCCACTAGGC GCTATTAATAGTTCCCTGCCCTATCAGAATATCCACCCGGTGACCATCGGCGAATGTCCT AAATATGTGCGGAGTGCCAAGCTGAGGATGGTCACTGGCTTACGTAACAATCCCTCAATT CAGAGCCGGGGCCTCTTTGGAGCAATCGCTGGATTCATCGAGGGGGGTTGGACCGGAATG ATCGACGGCTGGTACGGATATCATCACCAGAATGAACAAGGGTCTGGCTACGCCGCCGAC CAAAAATCTACCCAAAACGCTATTAATGGGATTACCAATAAGGTGAACACTGTAATAGAA AAAATGAATATTCAGTTTACTGCCGTTGGAAAGGAATTCAATAAGCTGGAGAAACGTATG GAGAATCTGAACAAGAAGGTAGATGACGGATTCCTGGACATCTGGACCTATAATGCAGAA TTGCTCGTTCTGCTTGAAAATGAGCGCACACTGGACTTTCATGACTCTAACGTCAAAAAT CTGTATGAAAAGGTCAAGTCCCAGCTGAAAAATAATGCGAAAGAGATTGGGAACGGATGT TTCGAATTCTACCACAAGTGTGACAACGAATGCATGGAGTCCGTACGGAACGGCACGTAC GACTACCCAAAATATTCTGAGGAAAGCAAGCTGAATAGAGAAAAGGTCGATGGGGTGAAA CTGGAGAGTATGGGAATCTATCAGATTCTCGCCATCTACTCCACTGTCGCCAGCTCCTTG GTACTTCTTGTTAGCTTGGGAGCCATATCATTCTGGATGTGCTCCAATGGATCCCTCCAA TGCAGAATCTGCATC 416 ATGAAAGCTAACCTTTTGGTGCTGCTCTGTGCCCTGGCAGCTGCCGATGCCGATACCATC TGTATCGGCTACCATGCTAATAATAGTACAGACACAGTGGACACCGTTCTGGAGAAAAAT GTCACCGTGACACATAGCGTGAACTTGCTGGAGGATTCTCACAACGGGAAGCTGTGCCGT CTGAAAGGGATTGCCCCTCTTCAGCTCGGTAAATGCAACATCGCCGGGTGGCTGCTAGGC AATCCAGAGTGTGATCCCCTGCTGCCGGTGAGAAGCTGGAGCTACATCGTGGAGACACCC AACTCCGAAAATGGCATTTGCTACCCCGGCGATTTCATCGACTACGAAGAACTGCGGGAG CAGCTGTCGTCTGTGAGCTCCTTCGAGAGATTCGAGATCTTTCCAAAAGAAAGCAGTTGG CCCAATCACAATACCAACGGCGTGACCGCTGCATGTAGTCACGAGGGCAAGAGCTCATTC TATAGAAACCTGTTGTGGCTGACAGAGAAGGAGGGGAGCTATCCCAAACTGAAGAATTCC TATGTGAATAAAAAGGGGAAGGAGGTTCTGGTATTATGGGGCATCCATCATCCTCCTAAC AGCAAAGAGCAGCAAAACCTTTATCAGAACGAGAATGCCTATGTATCGGTTGTTACCAGC AATTATAATCGGAGGTTTACCCCAGAGATAGCTGAGCGTCCAAAAGTGAGAGACCAAGCT GGCCGGATGAATTACTATTGGACCCTCCTCAAACCGGGCGATACCATCATTTTCGAAGCC AATGGCAACTTAATAGCGCCCATGTATGCTTTTGCCCTTTCGAGGGGATTTGGATCAGGT ATCATCACAAGCAACGCATCAATGCACGAGTGTAACACTAAGTGTCAGACTCCACTCGGG GCAATTAACAGCAGCCTACCTTACCAGAACATCCACCCCGTGACGATTGGAGAGTGTCCC AAGTACGTAAGGTCAGCCAAGCTCAGGATGGTTACAGGGCTGCGAAATAACCCCTCTATT CAGTCAAGGGGCTTGTTCGGCGCCATCGCCGGGTTTATCGAGGGCGGCTGGACCGGAATG ATCGACGGATGGTATGGCTACCATCACCAGAACGAACAAGGGTCTGGCTATGCTGCGGAT CAGAAGTCAACACAGAATGCTATAAATGGTATCACGAATAAGGTAAATACAGTCATTGAA AAGATGAATATCCAGTTTACGGCCGTTGGGAAGGAGTTCAACAAGCTTGAAAAGAGAATG GAAAATCTGAATAAAAAAGTGGACGACGGCTTTTTGGATATCTGGACATATAACGCGGAG CTGCTAGTGCTCCTGGAAAACGAGCGGACTCTTGACTTTCACGATTCCAACGTCAAGAAC CTCTATGAAAAGGTTAAATCACAATTGAAGAATAATGCTAAGGAGATTGGCAATGGGTGC TTTGAGTTCTACCATAAGTGTGACAACGAATGTATGGAGTCAGTCCGGAACGGTACTTAC GATTACCCCAAGTATTCGGAAGAGTCAAAGTTGAATAGAGAAAAAGTCGACGGCGTGAAA CTCGAGTCTATGGGCATTTACCAGATCCTTGCGATTTATAGCACCGTCGCCAGTAGCTTG GTACTCCTAGTATCTCTGGGTGCAATCTCCTTTTGGATGTGTTCTAACGGCAGCTTACAG TGCAGGATCTGCATT 417 ATGAAAGCTAACTTGCTTGTGTTGTTGTGCGCTTTGGCCGCTGCCGACGCCGACACTATT TGCATCGGGTATCACGCCAATAATTCCACAGATACCGTCGATACCGTGCTCGAGAAGAAC GTGACCGTCACTCACTCAGTGAACCTTCTGGAGGACTCCCATAACGGGAAGCTCTGTAGG TTGAAAGGAATCGCCCCACTGCAGCTTGGTAAATGCAATATAGCCGGTTGGCTGCTGGGA AACCCTGAGTGCGACCCACTCCTCCCCGTACGGTCTTGGAGCTACATCGTGGAGACGCCA AATTCCGAGAATGGAATCTGTTATCCCGGCGACTTTATCGATTATGAGGAGTTGCGCGAG CAGCTGAGTTCAGTTTCATCCTTTGAACGGTTCGAGATTTTTCCAAAAGAGTCTAGCTGG CCTAATCATAATACCAATGGGGTTACAGCCGCTTGCTCACATGAGGGGAAGTCCAGTTTC TATAGGAACCTGCTTTGGCTGACCGAGAAAGAGGGCTCCTATCCAAAGCTCAAGAACAGC TATGTAAATAAGAAAGGCAAGGAAGTGTTGGTCCTGTGGGGCATACACCACCCTCCCAAC TCGAAGGAGCAGCAAAACCTATACCAGAACGAGAATGCCTACGTCAGCGTGGTCACTAGC AATTACAATAGAAGGTTCACACCCGAAATTGCTGAGCGGCCGAAAGTGAGAGACCAGGCA GGACGAATGAACTACTATTGGACCCTGCTGAAGCCCGGGGATACAATCATTTTCGAGGCG AACGGGAACCTCATTGCCCCCATGTACGCTTTTGCCCTCAGCAGAGGCTTTGGGTCTGGT ATAATCACCAGTAACGCTAGCATGCATGAATGTAATACCAAGTGCCAGACACCCTTAGGG GCCATTAACTCATCTCTCCCATATCAGAACATACATCCTGTGACCATCGGTGAATGCCCG AAATACGTAAGGAGCGCAAAATTAAGGATGGTGACCGGTCTTAGGAACAATCCATCCATT CAGTCTCGAGGGCTTTTCGGCGCCATTGCTGGATTCATAGAAGGCGGATGGACAGGCATG ATCGATGGATGGTACGGTTATCACCACCAGAATGAGCAGGGGTCGGGCTACGCTGCCGAT CAGAAGTCTACCCAAAATGCCATCAATGGCATAACCAACAAGGTGAACACAGTTATCGAG AAAATGAACATACAGTTTACTGCAGTGGGAAAGGAGTTCAACAAACTGGAGAAACGAATG GAGAACTTGAATAAAAAAGTCGACGACGGCTTCCTTGATATTTGGACTTATAATGCCGAG CTTTTAGTCCTGTTAGAGAATGAACGTACATTGGACTTCCACGATAGCAACGTAAAGAAC CTCTATGAGAAAGTGAAAAGTCAGCTAAAAAATAATGCCAAAGAGATCGGGAATGGTTGT TTCGAGTTTTATCACAAGTGTGATAATGAGTGCATGGAGTCTGTGAGAAACGGCACGTAC GATTACCCTAAGTATTCTGAGGAGAGTAAGTTAAATCGCGAGAAAGTTGATGGTGTGAAG CTTGAGTCAATGGGCATCTACCAGATCCTGGCCATCTACTCCACCGTGGCGTCTTCTCTG GTGCTGCTTGTTAGCCTGGGTGCTATCTCCTTCTGGATGTGTTCTAACGGCTCCCTGCAG TGTAGGATCTGCATC 418 ATGAAAGCAAATCTGCTGGTGTTGCTGTGTGCCCTGGCTGCCGCAGACGCAGATACCATC TGTATCGGCTATCACGCTAATAACAGTACAGACACTGTGGATACTGTTCTCGAGAAGAAC GTCACTGTGACCCACTCAGTAAATTTACTCGAAGACAGTCACAACGGCAAGTTGTGTAGA CTCAAAGGCATTGCCCCTCTCCAGCTGGGAAAGTGCAACATTGCTGGATGGCTCCTGGGG AACCCCGAATGTGATCCGCTTTTGCCTGTGAGAAGCTGGTCCTACATAGTAGAAACCCCA AACTCCGAAAATGGTATTTGCTATCCGGGCGATTTTATAGATTATGAAGAATTAAGGGAG CAGTTGTCTTCCGTGTCCTCCTTCGAACGCTTCGAAATCTTCCCCAAAGAGAGTTCCTGG CCAAACCATAATACTAACGGGGTGACAGCGGCTTGCTCTCACGAAGGAAAATCTTCCTTC TACCGGAACCTGCTTTGGTTGACCGAGAAGGAGGGCAGTTACCCGAAATTGAAAAATAGT TACGTTAATAAGAAAGGGAAGGAAGTCCTGGTGTTATGGGGTATTCATCACCCCCCAAAC AGCAAGGAGCAGCAAAATTTGTACCAGAACGAGAATGCGTACGTGAGTGTGGTCACCAGT AATTACAACCGGAGGTTTACCCCCGAGATCGCAGAACGCCCGAAAGTACGGGACCAGGCA GGGAGGATGAATTACTATTGGACTCTTTTAAAGCCCGGGGATACCATCATCTTTGAGGCA AACGGTAACCTCATAGCTCCCATGTACGCCTTCGCCCTGAGCCGCGGTTTCGGCAGTGGC ATTATAACCTCTAACGCCAGCATGCACGAATGTAACACTAAATGTCAGACCCCTCTCGGC GCCATTAATAGCAGTCTCCCTTACCAAAATATCCACCCCGTTACCATTGGCGAGTGTCCA AAATACGTAAGGTCCGCAAAACTGCGCATGGTGACTGGACTGAGAAACAATCCCTCTATT CAGTCGAGGGGACTATTCGGAGCCATCGCTGGGTTTATCGAAGGGGGATGGACTGGAATG ATCGATGGTTGGTACGGGTACCACCACCAGAACGAGCAAGGCTCAGGGTATGCCGCAGAC CAGAAGAGTACCCAGAACGCCATCAACGGTATCACTAATAAGGTGAATACCGTCATCGAG AAGATGAATATCCAGTTTACCGCTGTGGGCAAAGAGTTTAATAAGCTGGAAAAGCGCATG GAGAACCTGAATAAGAAGGTTGACGACGGCTTCCTCGATATTTGGACTTATAACGCCGAG CTGCTCGTTCTCCTCGAAAATGAACGCACCCTTGACTTTCACGATTCAAACGTCAAGAAT CTGTATGAGAAGGTGAAGAGCCAGCTGAAGAATAACGCGAAGGAAATCGGGAACGGTTGT TTCGAATTTTACCACAAGTGCGATAATGAGTGCATGGAGAGCGTGCGAAATGGCACATAT GACTATCCTAAGTACAGCGAGGAAAGTAAACTCAACAGAGAAAAGGTTGATGGCGTCAAG CTCGAGTCAATGGGGATTTACCAGATTCTGGCCATCTATAGTACTGTGGCTTCCTCTCTG GTTTTGCTCGTTTCACTGGGAGCCATTTCTTTCTGGATGTGTTCGAACGGATCCCTCCAA TGCAGGATTTGTATT 419 ATGAAAGCAAATCTGCTCGTCCTCCTGTGCGCTCTTGCAGCCGCCGACGCCGACACCATA TGCATTGGATATCATGCTAACAACTCAACAGACACCGTGGACACTGTCCTAGAAAAAAAC GTGACCGTGACACACTCGGTCAATCTGTTAGAAGACAGCCATAACGGGAAGCTGTGCCGA CTCAAGGGAATAGCCCCCCTGCAGCTGGGCAAGTGCAATATCGCCGGGTGGCTCCTCGGC AACCCTGAGTGCGATCCCTTGCTTCCAGTTAGAAGTTGGTCCTATATCGTCGAAACTCCT AACTCAGAGAATGGAATTTGCTATCCCGGAGATTTCATCGACTACGAAGAGCTCAGAGAG CAACTTTCCAGTGTGTCAAGTTTCGAACGCTTTGAAATCTTCCCAAAGGAATCTTCATGG CCCAACCACAATACGAATGGAGTGACCGCCGCCTGTAGTCACGAGGGAAAAAGTAGCTTC TACCGCAATCTTTTGTGGCTGACCGAGAAGGAAGGAAGCTACCCAAAGCTGAAGAACTCC TACGTGAACAAAAAAGGTAAGGAGGTCCTGGTGCTGTGGGGGATTCACCATCCCCCTAAC AGTAAGGAGCAGCAAAATCTCTACCAGAACGAGAACGCTTACGTATCTGTTGTGACTTCT AATTATAACAGGAGGTTCACGCCAGAAATTGCTGAGAGGCCAAAGGTCAGGGACCAGGCT GGGCGCATGAACTACTACTGGACCCTGCTAAAGCCTGGTGACACTATCATCTTTGAGGCC AATGGAAATTTAATTGCACCCATGTACGCATTTGCCCTATCGCGCGGGTTCGGGAGCGGG ATAATTACCTCCAACGCATCGATGCATGAGTGCAACACAAAATGTCAAACACCTCTCGGG GCCATTAACAGCTCCCTCCCCTATCAGAATATTCACCCGGTAACAATCGGTGAATGTCCT AAGTACGTACGCTCCGCCAAGCTGAGGATGGTAACCGGTCTGCGGAATAATCCTAGCATC CAGTCCCGGGGTCTTTTCGGCGCCATCGCAGGTTTTATAGAAGGGGGCTGGACTGGTATG ATCGATGGATGGTACGGGTACCATCACCAAAATGAGCAAGGTTCGGGGTACGCAGCAGAC CAGAAATCAACCCAAAATGCCATTAACGGAATTACAAATAAGGTTAACACCGTTATCGAA AAGATGAATATCCAGTTTACAGCCGTAGGGAAAGAATTTAATAAGCTCGAGAAGCGGATG GAAAACCTGAACAAGAAAGTGGATGACGGGTTCCTTGACATCTGGACTTATAATGCAGAG CTATTAGTGCTGCTGGAGAACGAACGTACCCTGGATTTCCATGATTCAAACGTCAAAAAT CTTTATGAGAAAGTTAAGTCCCAGCTCAAGAATAATGCGAAGGAAATCGGCAACGGGTGT TTCGAATTCTATCACAAGTGCGATAACGAATGCATGGAGAGCGTTAGAAACGGCACCTAT GACTACCCCAAGTACAGCGAAGAGTCTAAGCTGAACCGGGAAAAGGTCGACGGTGTGAAA CTGGAATCCATGGGCATTTACCAGATCCTCGCTATTTACTCGACAGTCGCAAGTAGCCTG GTGCTTTTGGTTTCTCTCGGCGCAATCTCATTCTGGATGTGCTCCAACGGATCCCTCCAG TGTCGCATCTGTATC 420 ATGAAAGCTAACCTGCTGGTCCTTCTGTGCGCTCTCGCAGCAGCAGATGCGGACACCATC TGCATAGGATACCATGCTAATAATTCCACAGACACTGTGGACACAGTGCTGGAAAAGAAT GTAACGGTGACCCACAGCGTTAACTTGCTGGAGGATAGCCACAATGGTAAGCTTTGTCGT TTGAAAGGGATCGCACCCCTGCAGTTGGGCAAATGTAATATCGCCGGGTGGCTCCTGGGC AACCCGGAGTGCGACCCTTTGCTGCCCGTGCGGAGTTGGTCATACATTGTGGAAACTCCT AACAGTGAGAATGGTATTTGCTATCCTGGGGACTTCATTGACTATGAAGAACTTCGCGAA CAGTTATCTAGCGTGTCTAGCTTTGAACGCTTTGAGATCTTCCCAAAGGAGAGTAGTTGG CCTAACCATAACACCAACGGGGTCACAGCGGCCTGTTCGCACGAAGGCAAGTCCAGCTTT TATCGCAATCTGCTGTGGTTGACAGAGAAGGAGGGATCATACCCGAAGCTGAAAAATTCC TACGTGAACAAGAAGGGCAAAGAAGTACTGGTGTTATGGGGCATTCACCACCCACCAAAT AGCAAAGAGCAGCAGAACCTTTATCAGAACGAGAACGCCTACGTGAGCGTTGTTACGAGT AATTACAACCGCCGATTTACTCCCGAGATTGCGGAAAGGCCGAAGGTGAGAGACCAGGCA GGCCGCATGAACTATTACTGGACACTCCTGAAGCCTGGTGACACAATAATCTTCGAAGCT AACGGCAACCTGATAGCCCCAATGTACGCCTTTGCCCTAAGTAGAGGTTTCGGCTCTGGA ATTATTACGTCTAACGCCAGCATGCACGAGTGTAACACTAAATGCCAAACCCCACTAGGT GCTATTAACTCGTCTCTGCCGTACCAGAATATCCACCCAGTAACGATTGGAGAGTGCCCT AAATATGTGCGATCAGCAAAGCTTAGAATGGTGACTGGGTTACGCAACAATCCCTCTATT CAGTCCCGCGGCCTGTTTGGGGCGATAGCCGGATTCATCGAAGGGGGCTGGACGGGCATG ATTGACGGCTGGTATGGGTATCATCATCAGAACGAACAGGGATCAGGATACGCAGCTGAC CAAAAATCCACGCAGAACGCCATCAACGGGATCACGAATAAAGTGAATACAGTGATCGAG AAAATGAACATTCAGTTCACGGCAGTTGGAAAAGAGTTCAACAAACTTGAGAAGAGGATG GAGAACCTGAATAAAAAGGTGGACGACGGATTCCTGGATATATGGACTTACAATGCCGAA CTACTCGTCCTACTGGAAAATGAGCGAACGCTGGACTTCCATGATTCGAATGTCAAGAAT CTGTATGAAAAGGTCAAGTCCCAGCTGAAAAATAATGCTAAAGAGATAGGCAACGGGTGT TTCGAGTTTTACCATAAGTGCGATAATGAATGTATGGAGTCCGTGCGAAACGGTACTTAC GACTACCCAAAATACTCAGAGGAGTCCAAACTCAACAGGGAGAAAGTGGACGGGGTTAAG CTGGAAAGTATGGGTATTTATCAGATCCTGGCCATCTATTCTACAGTTGCATCTTCTCTA GTGCTGCTGGTATCTCTGGGCGCAATATCTTTTTGGATGTGTTCAAATGGGAGCCTGCAG TGCCGGATTTGTATC 421 ATGAAAGCAAATCTTCTGGTGTTACTGTGTGCTTTGGCAGCAGCCGATGCTGACACCATA TGTATTGGCTATCACGCAAACAATTCAACCGACACAGTCGACACCGTCCTCGAAAAGAAC GTTACCGTGACCCACTCAGTGAACCTCCTCGAGGACTCCCATAATGGCAAGCTGTGTAGG TTAAAGGGGATCGCCCCACTGCAGTTGGGAAAGTGTAATATTGCTGGGTGGCTTCTGGGT AACCCCGAATGCGATCCACTCCTCCCCGTTCGCAGCTGGAGTTACATTGTTGAAACCCCA AACAGCGAGAACGGTATCTGTTACCCAGGAGATTTTATTGATTACGAGGAGTTACGAGAA CAACTGTCCTCAGTGAGTTCTTTTGAAAGGTTTGAGATATTCCCTAAAGAGAGCAGCTGG CCGAATCATAACACCAATGGGGTGACTGCAGCTTGCTCCCACGAGGGGAAGTCCTCCTTC TATCGCAATCTGTTGTGGCTCACCGAAAAGGAGGGATCATATCCGAAGTTGAAAAATAGC TACGTTAATAAGAAGGGAAAAGAGGTGCTGGTGCTGTGGGGAATCCATCATCCACCTAAT TCCAAGGAGCAACAGAATCTATACCAAAACGAAAATGCTTACGTTTCTGTGGTGACCTCA AATTATAACCGCCGCTTCACTCCAGAGATCGCTGAGCGACCAAAAGTGCGGGACCAAGCC GGCAGAATGAATTACTATTGGACCTTGCTGAAACCCGGAGACACCATAATTTTTGAAGCC AATGGGAACCTGATTGCCCCTATGTACGCCTTCGCCCTGTCTAGGGGTTTCGGCAGCGGG ATCATAACATCTAACGCAAGCATGCACGAATGTAATACCAAGTGTCAGACCCCTCTGGGA GCCATTAATTCCAGTCTCCCATACCAGAACATCCACCCCGTTACCATTGGGGAGTGTCCG AAATACGTTAGAAGTGCCAAATTACGAATGGTGACAGGATTGCGGAACAACCCCAGCATC CAGAGCAGAGGCCTATTTGGCGCCATCGCAGGATTCATCGAAGGCGGATGGACCGGAATG ATCGACGGATGGTACGGGTATCACCACCAGAATGAACAGGGGTCGGGTTACGCCGCCGAC CAGAAATCTACCCAGAATGCCATTAATGGGATAACAAACAAGGTCAACACCGTGATTGAG AAGATGAATATACAGTTTACTGCCGTCGGCAAAGAGTTTAATAAACTGGAAAAGCGAATG GAAAACCTGAACAAGAAAGTCGACGATGGGTTCCTGGATATCTGGACATACAACGCTGAG TTGCTCGTGCTGCTCGAGAATGAGAGAACCTTGGACTTTCACGATTCAAACGTAAAAAAC TTATACGAAAAAGTCAAGAGTCAGCTGAAAAATAATGCCAAGGAAATCGGGAACGGATGC TTTGAGTTCTATCACAAGTGCGACAATGAGTGTATGGAATCCGTTAGGAACGGGACATAC GATTACCCAAAATACTCCGAGGAGAGCAAGTTAAACAGAGAAAAAGTTGACGGAGTGAAA CTAGAGTCCATGGGTATTTACCAGATCCTGGCCATTTATTCTACCGTCGCGTCATCACTG GTACTCCTTGTCTCCCTTGGAGCGATATCCTTCTGGATGTGTTCCAACGGCTCCCTTCAG TGCCGAATCTGCATT 422 ATGAAGGCTAATCTTCTGGTGTTACTGTGCGCCCTGGCTGCCGCCGACGCCGACACCATC TGCATTGGTTATCACGCTAATAACTCGACGGATACAGTGGATACTGTACTGGAAAAGAAC GTGACAGTCACCCACAGTGTTAACCTGCTCGAGGATAGTCACAATGGCAAGTTGTGCAGG CTGAAGGGGATCGCTCCCCTGCAACTCGGCAAGTGTAATATCGCCGGCTGGCTTTTAGGC AACCCCGAGTGCGACCCCCTACTGCCCGTTAGGTCCTGGAGCTACATCGTGGAAACTCCT AACAGCGAGAACGGCATCTGCTATCCTGGGGACTTCATCGATTACGAAGAGCTCCGGGAA CAGCTCTCTTCCGTGAGCTCCTTTGAGAGATTTGAGATCTTCCCTAAGGAATCGTCCTGG CCTAACCACAATACAAATGGCGTGACAGCTGCCTGTTCACACGAAGGGAAAAGTTCCTTC TATAGGAATCTGCTGTGGCTGACAGAGAAAGAGGGCTCTTATCCTAAATTAAAGAACTCC TACGTGAACAAGAAGGGTAAAGAGGTCTTAGTGCTGTGGGGCATTCACCATCCCCCCAAT TCCAAGGAGCAGCAAAATCTGTACCAGAACGAGAACGCTTATGTGTCCGTCGTTACTTCT AACTATAATAGGCGTTTCACCCCGGAGATTGCTGAGAGGCCTAAGGTACGGGACCAGGCC GGTAGAATGAATTACTACTGGACACTACTTAAGCCAGGTGACACAATCATCTTTGAGGCA AACGGAAACCTAATCGCTCCAATGTATGCATTTGCCCTGAGCCGCGGATTCGGTAGCGGA ATTATCACCAGCAATGCCTCTATGCACGAGTGCAATACTAAGTGTCAGACTCCTTTGGGA GCGATCAACTCCAGCTTGCCATACCAAAACATTCACCCGGTGACTATTGGTGAATGCCCC AAGTACGTGCGGTCTGCAAAACTGAGAATGGTTACCGGACTCCGGAATAACCCTAGTATA CAGTCTAGGGGGCTCTTTGGAGCCATTGCAGGTTTCATCGAAGGCGGCTGGACCGGCATG ATCGACGGATGGTATGGTTATCACCACCAAAACGAGCAGGGATCAGGATATGCTGCAGAT CAAAAATCTACTCAAAATGCAATAAACGGTATCACCAATAAGGTGAACACCGTAATCGAA AAAATGAACATCCAGTTTACAGCCGTGGGCAAGGAGTTTAATAAGCTGGAGAAACGCATG GAGAACCTCAATAAGAAGGTTGACGATGGATTCCTGGACATCTGGACGTATAATGCCGAG CTCCTGGTACTGCTCGAGAATGAACGAACCCTCGACTTCCATGATAGCAACGTGAAGAAC TTATATGAGAAGGTGAAGTCACAACTGAAAAACAATGCTAAGGAAATAGGCAACGGATGT TTTGAATTCTACCACAAGTGTGACAACGAATGTATGGAATCGGTGAGGAATGGGACATAT GACTACCCCAAGTACTCGGAAGAAAGTAAGCTTAATAGGGAGAAGGTGGACGGCGTGAAA CTCGAGAGCATGGGGATTTACCAAATCCTAGCAATCTATTCCACAGTTGCTTCTTCTCTG GTGCTCCTTGTGTCACTTGGGGCGATTTCGTTCTGGATGTGCTCAAACGGGAGCCTCCAG TGCCGGATCTGCATC 423 ATGAAGGCAAACCTGCTGGTCCTGCTCTGCGCACTGGCCGCGGCAGACGCCGACACAATC TGCATAGGCTATCACGCAAATAACAGTACTGACACCGTCGATACAGTCCTGGAGAAAAAC GTGACTGTGACCCACAGCGTAAATCTGCTGGAAGACAGCCACAATGGAAAATTGTGCAGA TTGAAAGGAATAGCACCCCTGCAATTGGGGAAATGTAATATTGCCGGATGGCTGCTCGGC AACCCCGAATGCGACCCGCTGCTGCCCGTCCGGTCTTGGAGTTATATCGTTGAGACACCG AACTCCGAGAATGGTATCTGCTATCCGGGCGACTTCATCGACTATGAGGAACTCAGAGAG CAGCTGTCATCTGTGTCTTCATTCGAGCGTTTCGAGATTTTCCCAAAGGAGTCATCGTGG CCCAACCATAACACAAACGGAGTCACGGCAGCATGCTCTCACGAAGGGAAAAGCTCTTTC TACCGCAACCTGCTCTGGTTGACTGAGAAAGAGGGGTCTTACCCCAAACTTAAGAACAGC TACGTGAACAAGAAGGGCAAGGAGGTCTTGGTACTGTGGGGCATCCATCACCCACCTAAT AGTAAAGAGCAACAAAACCTATACCAGAACGAGAACGCATACGTGTCAGTAGTCACCTCT AATTACAACAGGCGGTTTACACCAGAGATAGCTGAGCGGCCAAAGGTCCGGGACCAGGCA GGCAGGATGAACTACTATTGGACTTTGTTAAAGCCTGGAGACACCATCATCTTTGAGGCT AACGGGAATCTGATTGCTCCCATGTATGCTTTTGCACTTTCCAGAGGCTTTGGATCCGGT ATTATCACATCGAATGCGTCCATGCATGAGTGTAACACTAAGTGTCAAACACCACTCGGC GCAATCAATTCTTCACTTCCTTATCAAAATATTCACCCCGTGACCATCGGCGAGTGCCCC AAGTATGTCAGGAGCGCTAAGCTGCGGATGGTGACAGGGTTGAGGAATAATCCTTCAATT CAGTCGAGGGGATTATTCGGTGCCATCGCGGGATTCATTGAGGGGGGGTGGACAGGAATG ATAGACGGGTGGTATGGTTACCACCATCAGAACGAGCAGGGGTCAGGCTACGCCGCTGAC CAAAAATCCACCCAAAATGCCATCAATGGAATCACAAATAAGGTAAATACAGTGATCGAA AAAATGAACATTCAATTCACAGCTGTCGGAAAGGAGTTCAATAAGCTTGAGAAACGAATG GAGAACTTAAATAAAAAAGTTGACGACGGTTTCCTGGACATTTGGACATACAACGCAGAA CTGCTCGTTTTACTAGAGAACGAACGGACGCTGGACTTTCATGATTCTAACGTAAAGAAC TTGTACGAGAAGGTGAAAAGCCAGCTTAAAAATAACGCCAAAGAAATCGGAAACGGCTGC TTCGAATTCTACCACAAATGTGATAACGAGTGCATGGAGAGCGTGAGGAATGGGACATAT GACTATCCCAAATATTCTGAAGAGTCAAAACTGAATCGGGAAAAGGTCGATGGTGTCAAA CTGGAGTCTATGGGCATCTATCAGATACTGGCAATCTACTCCACCGTGGCCAGCAGTCTC GTGCTGCTGGTGAGCCTGGGCGCAATAAGCTTCTGGATGTGCTCAAACGGAAGCCTGCAA TGTAGGATTTGTATC 424 ATGAAGGCCAATCTCCTGGTGCTGTTGTGCGCACTGGCAGCGGCGGATGCAGATACAATA TGTATCGGATATCACGCAAATAACAGCACAGATACAGTGGACACCGTGCTGGAGAAGAAT GTGACTGTGACGCATAGTGTTAACCTCTTGGAAGATAGCCACAATGGCAAGCTGTGTCGC TTGAAGGGAATCGCCCCCCTGCAGCTCGGGAAATGCAATATCGCGGGATGGCTTCTGGGT AACCCTGAATGCGACCCGCTGCTGCCCGTGCGCTCATGGTCATACATTGTGGAGACACCT AATTCAGAGAATGGGATTTGCTATCCTGGGGACTTTATCGATTACGAGGAACTGAGAGAG CAGCTATCTTCAGTTAGTTCCTTCGAACGATTCGAGATCTTTCCAAAGGAGAGTAGCTGG CCCAATCATAACACTAACGGAGTGACCGCCGCGTGCAGCCACGAGGGCAAATCCTCATTT TACCGAAACCTGTTATGGCTCACAGAAAAGGAGGGGTCTTACCCGAAGCTGAAAAACTCT TATGTGAACAAGAAGGGGAAAGAGGTGTTAGTTCTGTGGGGCATTCACCACCCTCCAAAT TCCAAGGAACAACAAAACCTTTACCAAAACGAGAATGCATATGTCTCGGTCGTGACGTCG AACTATAATAGAAGATTTACCCCCGAGATTGCTGAACGACCCAAGGTGAGAGATCAGGCG GGAAGAATGAACTATTACTGGACCTTGCTCAAACCGGGAGATACAATCATATTCGAGGCT AACGGAAACTTGATCGCCCCAATGTACGCCTTTGCCCTCTCCCGCGGTTTCGGGAGCGGT ATCATCACCTCAAATGCTTCTATGCATGAATGCAATACCAAATGTCAAACACCTCTGGGC GCAATCAACTCGAGCCTGCCTTATCAGAACATTCACCCTGTCACCATTGGTGAGTGCCCC AAGTACGTAAGATCAGCTAAGCTGCGTATGGTGACCGGGCTGAGAAACAATCCCTCCATC CAAAGTCGCGGTTTATTCGGCGCCATTGCCGGGTTCATAGAGGGTGGGTGGACAGGAATG ATCGATGGCTGGTATGGATATCATCATCAGAACGAACAAGGATCAGGGTATGCAGCAGAC CAGAAGTCTACTCAAAACGCAATTAATGGCATCACCAATAAGGTTAACACTGTCATAGAA AAGATGAACATCCAGTTCACTGCGGTGGGCAAAGAGTTTAACAAGCTCGAGAAGCGGATG GAGAACCTCAATAAGAAAGTCGATGACGGATTCCTGGATATATGGACATATAATGCCGAG CTGCTGGTGCTGCTGGAAAACGAAAGAACCCTCGATTTCCACGACTCTAATGTGAAGAAT CTGTACGAGAAGGTCAAGTCCCAGCTGAAAAATAACGCCAAGGAGATAGGGAACGGCTGC TTTGAATTCTATCACAAGTGCGACAATGAGTGCATGGAGAGCGTTCGGAACGGGACTTAC GATTATCCGAAGTATTCAGAGGAGAGCAAGCTTAATCGTGAAAAGGTCGACGGAGTGAAA TTAGAAAGTATGGGAATCTATCAGATTCTTGCAATCTATAGCACCGTTGCCAGCTCTCTG GTGTTACTGGTAAGCCTCGGGGCAATATCTTTTTGGATGTGTAGCAATGGGTCTCTCCAG TGTCGAATTTGTATT 425 ATGAAGGCCAACCTGCTCGTGCTTCTGTGTGCGCTGGCCGCCGCCGACGCAGACACTATC TGTATCGGCTATCACGCCAATAACAGCACGGATACCGTGGATACCGTATTGGAGAAAAAT GTCACGGTAACACACTCTGTGAATCTGCTTGAAGACTCCCATAACGGAAAACTTTGTCGG CTCAAGGGCATTGCCCCTCTGCAACTGGGCAAGTGCAACATCGCCGGGTGGCTGCTGGGC AATCCGGAGTGCGACCCTCTCCTGCCAGTCAGGTCCTGGTCCTATATCGTAGAAACCCCC AATAGTGAAAACGGCATATGCTACCCAGGTGATTTCATCGATTATGAAGAGCTCAGAGAG CAACTGAGCTCCGTCAGCAGTTTTGAGCGGTTCGAGATTTTCCCAAAGGAATCATCATGG CCGAATCACAACACCAATGGAGTGACCGCAGCGTGTTCTCATGAGGGGAAGAGCTCGTTC TATCGGAACCTGCTTTGGTTGACGGAGAAGGAGGGGTCATACCCCAAACTTAAGAACTCA TACGTGAATAAAAAGGGCAAGGAGGTCCTCGTGCTGTGGGGGATTCACCACCCCCCCAAT TCCAAGGAGCAGCAGAATCTGTACCAAAACGAGAATGCTTATGTGAGTGTGGTGACGTCT AATTATAATAGACGGTTTACACCTGAGATCGCAGAAAGACCCAAAGTGCGCGACCAGGCT GGGAGGATGAATTACTATTGGACTCTGTTAAAGCCCGGCGATACCATCATTTTCGAGGCA AATGGGAATCTTATCGCTCCAATGTACGCCTTCGCCCTGTCACGGGGGTTCGGGAGCGGG ATTATCACATCAAATGCCAGCATGCATGAATGCAACACTAAGTGCCAGACCCCACTGGGC GCCATCAATTCCAGCCTCCCTTACCAGAACATACACCCTGTTACAATAGGAGAGTGCCCC AAGTACGTCCGATCCGCTAAACTGCGGATGGTTACAGGCCTACGTAATAATCCTAGCATT CAGTCACGGGGACTGTTTGGCGCAATAGCCGGGTTCATCGAGGGCGGGTGGACCGGAATG ATTGATGGGTGGTACGGATACCACCATCAGAATGAGCAGGGATCTGGGTACGCCGCCGAC CAGAAGAGCACACAGAATGCCATTAATGGCATAACCAACAAAGTGAACACCGTGATCGAG AAGATGAACATTCAATTTACGGCTGTAGGTAAGGAATTCAACAAACTGGAGAAACGGATG GAGAATTTGAACAAGAAGGTCGATGATGGGTTCCTCGATATTTGGACCTACAACGCTGAG CTTTTGGTGCTGCTGGAGAACGAGAGGACACTTGATTTTCATGATTCGAATGTGAAAAAC TTGTACGAAAAGGTCAAGTCACAGCTGAAGAACAACGCTAAAGAGATTGGAAATGGATGC TTCGAGTTTTATCACAAATGCGACAATGAATGTATGGAGAGTGTGCGGAACGGAACATAC GATTACCCCAAATATTCCGAGGAGTCTAAGCTTAACCGTGAGAAGGTCGATGGCGTTAAG TTAGAGTCCATGGGAATCTACCAGATCCTGGCTATATATAGCACCGTCGCAAGCTCTCTA GTCTTGCTCGTCTCACTGGGAGCAATCTCGTTTTGGATGTGCTCTAACGGGTCCCTACAG TGTCGGATTTGCATC 426 ATGAAAGCTAATCTGCTGGTCCTGTTGTGTGCACTGGCGGCTGCAGATGCGGATACCATT TGTATCGGTTATCACGCTAATAACTCTACTGACACAGTCGACACGGTGTTGGAAAAGAAC GTCACAGTCACCCACAGCGTCAATCTGCTCGAAGATTCACACAACGGAAAGCTATGTAGG TTAAAGGGTATTGCACCATTGCAACTGGGAAAGTGTAACATTGCTGGATGGCTGCTGGGG AACCCCGAGTGTGATCCTTTGCTCCCTGTCAGATCCTGGTCCTACATTGTGGAAACCCCT AACTCAGAGAACGGGATCTGCTATCCAGGAGATTTTATCGACTATGAAGAGCTGAGGGAA CAACTATCCAGCGTCTCCAGCTTTGAGAGGTTCGAGATATTCCCTAAGGAGTCAAGCTGG CCAAATCACAATACAAACGGTGTCACAGCCGCCTGCAGTCACGAAGGCAAGTCATCGTTC TACCGAAATTTGTTGTGGTTGACGGAAAAAGAGGGATCATACCCAAAACTCAAGAATAGC TATGTCAACAAGAAAGGCAAGGAAGTGCTTGTCCTCTGGGGCATACATCATCCTCCTAAC TCTAAGGAGCAGCAAAACTTATACCAGAACGAGAACGCCTATGTGAGTGTGGTCACCAGC AATTATAATCGCAGGTTCACGCCTGAGATTGCCGAGAGGCCAAAAGTCAGAGACCAGGCC GGCAGGATGAATTACTATTGGACATTACTGAAACCAGGCGATACTATTATCTTCGAGGCT AACGGAAATCTGATAGCACCAATGTACGCCTTTGCCTTGTCCCGTGGGTTCGGCTCTGGG ATCATAACATCCAACGCAAGCATGCATGAGTGCAACACAAAGTGCCAGACACCGCTTGGA GCCATTAATTCTTCTCTGCCATATCAGAACATTCATCCTGTAACAATCGGGGAATGCCCA AAGTACGTTAGAAGTGCCAAGCTGCGCATGGTGACCGGCCTGAGGAATAATCCCTCTATT CAGTCCAGAGGACTGTTCGGAGCCATCGCTGGGTTTATTGAGGGCGGCTGGACCGGAATG ATAGATGGCTGGTACGGGTACCACCACCAGAATGAACAGGGCTCTGGCTATGCCGCGGAC CAGAAATCTACCCAAAATGCCATCAATGGAATCACCAATAAAGTTAACACGGTGATTGAG AAAATGAACATTCAATTTACCGCGGTAGGAAAGGAGTTTAATAAGCTTGAGAAGCGTATG GAGAATTTGAACAAGAAGGTGGATGACGGTTTCCTCGATATTTGGACCTATAATGCCGAA CTACTAGTTTTATTGGAGAACGAACGCACACTGGATTTCCACGACTCTAATGTTAAAAAT CTGTACGAGAAAGTGAAGTCACAGCTAAAGAATAATGCCAAGGAAATAGGAAATGGATGC TTTGAATTTTACCACAAATGTGACAACGAATGCATGGAATCTGTGCGGAATGGAACTTAC GATTACCCTAAGTACTCTGAGGAGAGTAAACTGAACAGAGAGAAGGTAGACGGCGTAAAG CTCGAATCAATGGGAATCTACCAAATTCTGGCCATCTACTCTACCGTCGCCTCCTCTCTG GTTTTATTGGTCTCTCTTGGAGCCATTAGTTTCTGGATGTGCAGTAACGGCTCCCTGCAG TGCAGGATTTGTATC 427 ATGAAGGCCAACCTCCTCGTGCTGCTCTGCGCCTTGGCAGCCGCAGACGCCGATACCATC TGTATAGGGTACCACGCCAACAATTCAACAGATACCGTCGATACCGTACTGGAGAAAAAC GTCACCGTCACGCACAGCGTTAACCTGTTGGAAGATAGTCATAATGGAAAGCTCTGTCGC CTAAAAGGAATCGCGCCTCTGCAGCTGGGAAAGTGCAACATAGCCGGGTGGCTCCTCGGG AACCCGGAGTGTGACCCTCTTTTGCCGGTGCGCTCATGGTCATATATTGTTGAGACCCCT AACAGCGAAAACGGAATATGTTACCCAGGGGACTTCATCGATTATGAGGAATTACGAGAA CAACTAAGTTCCGTCTCTTCCTTCGAGCGCTTTGAAATCTTTCCTAAAGAGAGTTCCTGG CCCAACCACAACACTAATGGCGTGACAGCTGCTTGCAGTCATGAGGGCAAAAGTTCATTC TATAGAAATCTTCTCTGGCTAACTGAGAAAGAAGGATCCTACCCTAAACTCAAAAATTCC TATGTTAACAAGAAGGGCAAAGAGGTGCTCGTGCTGTGGGGGATCCACCACCCACCAAAT TCAAAAGAGCAACAAAACCTCTACCAGAATGAAAATGCCTACGTGAGCGTTGTGACTTCA AATTACAATAGACGGTTTACCCCAGAGATCGCAGAACGCCCTAAGGTACGTGATCAGGCT GGGCGAATGAACTACTACTGGACACTCCTCAAACCAGGCGACACTATAATCTTCGAGGCT AACGGCAACCTGATTGCTCCAATGTACGCGTTCGCTCTTTCACGCGGATTCGGCTCCGGC ATCATTACTAGTAATGCATCTATGCATGAATGCAATACTAAGTGCCAGACCCCACTCGGA GCCATAAACAGTTCTCTGCCATATCAGAACATACACCCTGTGACTATAGGAGAATGCCCA AAATATGTTCGGTCCGCTAAGCTGCGCATGGTGACCGGACTCCGGAACAACCCATCCATA CAATCACGGGGGCTGTTTGGCGCCATTGCCGGCTTCATCGAGGGTGGATGGACTGGTATG ATCGATGGTTGGTATGGATACCATCATCAGAATGAACAGGGCTCCGGCTATGCCGCCGAT CAGAAGTCCACCCAGAACGCCATTAACGGAATTACCAACAAGGTTAATACTGTGATCGAG AAGATGAATATTCAGTTCACAGCAGTCGGGAAGGAATTCAACAAACTGGAGAAACGTATG GAAAATCTCAACAAGAAGGTGGACGATGGGTTTTTAGACATTTGGACTTATAATGCCGAA CTGCTGGTGCTGCTGGAAAACGAGAGAACGTTGGACTTTCACGACAGCAACGTGAAAAAC CTGTATGAAAAAGTGAAGTCCCAGCTCAAAAACAATGCAAAGGAAATCGGCAACGGTTGC TTTGAGTTCTACCATAAGTGCGACAACGAATGTATGGAATCTGTGCGCAATGGAACCTAC GACTATCCTAAGTATAGCGAAGAATCTAAATTAAATAGGGAAAAGGTTGATGGAGTGAAA CTGGAGTCTATGGGGATCTACCAGATCCTTGCTATCTACTCAACCGTCGCTAGCTCCCTC GTACTGCTGGTCAGTTTAGGAGCGATATCTTTCTGGATGTGTTCTAATGGGTCACTGCAG TGTAGAATTTGCATC 428 ATGAAGGCCAATCTGCTGGTGCTTCTCTGCGCCTTAGCCGCCGCCGATGCAGATACCATT TGTATTGGATATCACGCTAACAACAGTACAGATACTGTGGACACTGTCCTGGAAAAGAAC GTCACCGTCACGCATAGCGTAAACCTGCTCGAGGACTCACACAACGGGAAGCTCTGTCGT CTGAAGGGCATCGCCCCCCTGCAGCTCGGCAAATGCAACATTGCGGGATGGCTTCTTGGA AACCCCGAGTGTGATCCCTTATTACCAGTGCGCTCTTGGTCCTATATAGTAGAAACCCCA AACAGCGAGAACGGGATTTGTTACCCCGGCGATTTCATAGACTACGAGGAGTTGCGCGAA CAGCTGTCTAGCGTCTCCTCATTCGAACGTTTCGAGATTTTCCCAAAGGAATCCTCGTGG CCCAATCATAATACCAATGGAGTCACTGCCGCCTGCAGCCACGAGGGAAAGTCATCTTTC TATCGGAATCTGCTCTGGCTGACCGAAAAGGAGGGATCTTATCCTAAACTGAAAAATTCT TACGTCAATAAGAAAGGCAAGGAAGTCTTAGTATTATGGGGAATTCATCACCCTCCCAAC AGTAAGGAGCAGCAGAACCTGTACCAGAACGAGAACGCCTATGTTTCTGTCGTGACATCT AACTATAACAGACGTTTCACCCCAGAAATTGCTGAAAGGCCAAAGGTCCGTGATCAGGCC GGCAGGATGAATTACTACTGGACTCTTCTGAAGCCTGGTGACACAATCATTTTCGAAGCC AACGGCAACCTGATTGCTCCCATGTACGCGTTCGCTCTGAGTCGCGGCTTTGGATCGGGT ATTATTACGTCCAATGCCTCTATGCATGAATGCAATACTAAATGTCAGACCCCTCTAGGC GCCATCAATTCTAGCCTCCCGTACCAGAACATTCATCCTGTGACTATTGGTGAATGCCCA AAGTACGTGAGGTCCGCCAAGCTTCGCATGGTGACCGGCCTGCGTAACAACCCCTCCATC CAATCCAGAGGTCTCTTTGGGGCAATCGCCGGTTTTATTGAGGGTGGTTGGACCGGAATG ATCGATGGTTGGTACGGGTACCACCATCAGAATGAGCAGGGCAGTGGATATGCCGCTGAC CAAAAATCTACACAAAACGCGATCAATGGAATCACCAATAAAGTGAACACAGTCATAGAA AAAATGAACATCCAGTTTACTGCGGTCGGGAAGGAATTTAATAAGCTCGAGAAAAGAATG GAAAATCTAAACAAAAAGGTCGATGACGGTTTCCTCGATATCTGGACATACAATGCCGAA TTACTGGTCCTGCTCGAGAATGAGCGGACATTAGACTTCCACGACAGCAATGTAAAGAAC CTTTACGAGAAGGTGAAGTCCCAGCTGAAGAACAATGCTAAAGAGATTGGGAATGGCTGT TTTGAATTTTACCATAAATGCGACAACGAGTGTATGGAAAGCGTGCGGAACGGGACTTAC GATTACCCAAAATATAGTGAGGAGAGCAAATTAAACCGTGAGAAGGTCGACGGGGTGAAG TTGGAATCCATGGGCATTTACCAAATCCTCGCAATTTACTCCACCGTGGCTTCTTCATTG GTTCTCCTGGTGTCCCTTGGGGCCATATCATTTTGGATGTGCTCTAATGGGAGTCTCCAG TGCCGTATATGCATT 429 ATGAAGGCTAACCTACTGGTTCTGCTGTGTGCGCTTGCCGCCGCAGATGCCGACACCATC TGCATCGGGTATCACGCAAATAACTCCACCGACACAGTAGACACAGTATTGGAAAAAAAC GTGACCGTCACCCACTCTGTGAACCTGCTCGAAGATAGCCATAATGGCAAATTGTGTAGA CTCAAAGGTATCGCTCCCTTGCAGCTAGGAAAGTGCAACATTGCAGGATGGCTCCTCGGC AACCCTGAGTGTGACCCCCTCCTGCCCGTCCGATCCTGGTCCTACATCGTGGAGACTCCA AACTCGGAGAACGGAATATGTTATCCTGGGGATTTCATTGACTATGAGGAGCTTAGGGAG CAACTATCCAGCGTATCTAGTTTCGAACGGTTCGAGATCTTTCCAAAAGAGTCCAGTTGG CCTAACCATAACACGAACGGTGTGACCGCTGCTTGTAGCCATGAGGGGAAATCATCTTTC TATCGCAACTTGCTTTGGCTCACAGAGAAGGAGGGCTCCTACCCTAAGTTGAAAAACAGC TATGTCAATAAAAAAGGCAAAGAGGTTCTCGTGTTATGGGGTATTCACCACCCTCCTAAC TCTAAAGAGCAACAAAATCTGTATCAGAACGAGAATGCGTATGTGTCAGTCGTTACATCA AATTACAATAGGCGGTTTACACCAGAGATCGCTGAAAGACCTAAAGTTCGGGACCAGGCC GGCCGCATGAATTACTACTGGACTCTGCTGAAGCCAGGGGATACGATTATCTTTGAAGCT AATGGTAACCTGATTGCTCCCATGTACGCCTTTGCCTTATCAAGAGGATTTGGATCCGGC ATAATCACATCCAATGCTAGCATGCACGAGTGCAACACCAAATGCCAGACTCCTTTGGGA GCCATCAACTCTAGTCTGCCATATCAGAATATCCATCCTGTGACCATCGGGGAGTGCCCG AAGTATGTGCGATCAGCCAAGCTGCGGATGGTCACCGGATTAAGAAATAACCCCTCCATT CAGTCTCGAGGACTGTTCGGTGCTATCGCTGGTTTTATTGAAGGTGGTTGGACAGGCATG ATCGATGGCTGGTACGGTTATCACCACCAGAACGAACAGGGGTCTGGGTACGCTGCCGAT CAGAAGAGTACCCAGAACGCGATCAATGGCATTACCAACAAAGTGAACACAGTAATAGAA AAGATGAACATTCAGTTCACCGCTGTTGGTAAAGAGTTCAACAAGCTGGAAAAACGGATG GAGAATCTCAACAAAAAGGTTGATGATGGGTTCCTGGATATCTGGACCTACAACGCGGAA CTGCTGGTACTGCTGGAAAATGAACGGACACTTGACTTTCACGACTCTAACGTGAAGAAT CTGTACGAAAAGGTAAAATCACAGCTAAAGAACAATGCAAAGGAGATTGGGAATGGATGC TTCGAGTTCTACCATAAGTGCGACAACGAGTGTATGGAGTCTGTGCGGAATGGCACTTAC GATTACCCTAAGTACTCCGAGGAATCTAAACTGAATCGAGAGAAAGTGGATGGTGTAAAG CTCGAGAGTATGGGCATTTATCAGATTCTGGCTATCTACTCGACTGTAGCCTCCTCACTG GTGTTACTGGTGAGCCTCGGTGCAATCTCATTCTGGATGTGTAGTAACGGCTCCTTACAG TGTCGCATTTGTATC 430 ATGAAGGCCAACTTGTTAGTCCTGCTGTGCGCTTTAGCGGCTGCCGACGCCGATACAATC TGTATTGGCTATCACGCTAACAATAGCACTGACACAGTCGATACAGTTCTGGAGAAGAAT GTTACAGTCACGCATAGCGTGAACTTACTGGAAGACTCTCACAATGGCAAGTTGTGTCGG CTGAAGGGGATCGCTCCATTGCAACTCGGAAAATGCAATATAGCGGGCTGGCTGCTCGGA AATCCAGAATGTGATCCCCTTCTGCCTGTCCGCTCCTGGTCCTACATCGTGGAGACTCCT AATTCTGAGAACGGAATATGCTACCCTGGCGACTTCATCGACTACGAAGAACTCCGGGAA CAGCTCTCTAGCGTGAGTTCCTTTGAGAGATTCGAAATTTTTCCAAAAGAGTCCAGCTGG CCTAATCATAATACAAACGGCGTGACTGCTGCATGCAGCCACGAAGGGAAATCGTCTTTT TATAGAAATCTGCTGTGGCTGACGGAGAAAGAAGGATCATACCCAAAGCTAAAGAACTCA TATGTTAACAAGAAAGGGAAGGAGGTGCTGGTGCTGTGGGGGATACATCACCCACCCAAT TCTAAAGAGCAGCAGAACTTGTATCAGAACGAAAATGCCTACGTGAGCGTCGTGACTTCC AACTATAACCGAAGATTCACTCCCGAAATTGCCGAACGCCCCAAGGTCCGGGATCAGGCG GGACGCATGAATTACTATTGGACCCTGCTGAAACCTGGAGACACTATTATCTTCGAGGCC AACGGCAACTTGATCGCTCCCATGTATGCCTTTGCCCTGAGTCGAGGTTTTGGAAGCGGG ATTATCACTTCCAATGCATCAATGCATGAATGCAATACAAAGTGTCAGACACCCCTTGGC GCAATTAACTCATCTCTGCCCTACCAGAACATTCATCCAGTCACTATCGGGGAGTGCCCT AAATATGTTAGATCTGCCAAGCTGCGGATGGTGACAGGGCTTAGAAATAACCCCAGCATT CAGAGCCGCGGCTTGTTTGGAGCCATTGCTGGGTTTATTGAGGGAGGGTGGACCGGAATG ATAGACGGTTGGTACGGGTACCATCATCAGAATGAGCAGGGCAGTGGGTACGCCGCTGAC CAAAAGAGCACCCAGAACGCTATCAACGGAATTACCAATAAGGTCAATACAGTGATAGAA AAGATGAACATTCAGTTTACTGCTGTGGGGAAGGAGTTCAATAAACTGGAAAAACGGATG GAGAACCTCAACAAGAAAGTGGACGACGGATTTCTGGACATTTGGACCTATAACGCCGAG TTACTGGTACTGCTTGAAAACGAAAGGACCTTAGACTTTCATGATTCTAATGTTAAAAAT CTGTATGAAAAGGTCAAGAGCCAACTTAAGAACAACGCCAAAGAAATCGGAAACGGTTGC TTCGAGTTTTATCATAAGTGTGACAATGAGTGCATGGAGTCTGTTCGAAATGGTACATAC GACTATCCCAAGTATAGTGAAGAGAGCAAACTTAATCGGGAGAAGGTGGATGGCGTGAAA CTGGAAAGCATGGGAATCTACCAGATCTTAGCCATATACAGTACAGTCGCTTCATCTCTC GTGCTTCTCGTCAGCCTCGGAGCAATCAGCTTTTGGATGTGTAGCAACGGCAGCCTCCAA TGCCGAATCTGCATC 431 ATGAAGGCAAACCTCCTTGTCCTCCTGTGTGCACTGGCAGCCGCCGACGCCGACACTATT TGTATCGGGTACCATGCAAATAACTCCACCGATACCGTGGACACAGTCCTGGAAAAAAAC GTGACAGTGACGCATTCAGTGAATCTCCTTGAAGATAGCCACAATGGAAAGTTGTGCCGG CTGAAAGGAATCGCACCTTTACAGCTGGGAAAGTGTAACATTGCAGGGTGGCTGTTGGGG AACCCTGAGTGTGACCCCCTCTTACCCGTCCGGTCTTGGAGTTACATAGTGGAAACACCA AATAGTGAGAACGGCATCTGCTACCCAGGAGATTTCATCGATTATGAAGAGCTGCGTGAA CAACTCTCTAGTGTTAGTTCTTTCGAAAGGTTCGAGATCTTTCCTAAAGAATCGTCATGG CCCAATCACAATACAAACGGGGTCACAGCTGCTTGCTCACACGAAGGAAAGAGCAGTTTC TATAGAAATCTGCTGTGGCTGACCGAGAAGGAGGGTTCTTACCCTAAACTTAAAAATTCT TATGTTAACAAGAAGGGCAAAGAAGTGCTTGTCCTGTGGGGCATCCACCATCCCCCTAAC TCTAAAGAGCAGCAGAACTTGTACCAGAATGAGAACGCCTATGTGTCAGTGGTTACCTCA AATTATAACCGGAGATTTACGCCTGAGATCGCCGAGCGGCCCAAAGTGCGGGATCAAGCC GGACGTATGAACTACTATTGGACACTCCTTAAGCCAGGCGATACCATTATCTTTGAGGCA AATGGCAACCTGATCGCACCCATGTACGCGTTCGCCTTGTCTCGAGGATTCGGCAGCGGC ATCATCACGTCCAACGCCAGTATGCATGAGTGTAATACAAAATGCCAAACTCCCCTCGGG GCAATTAACTCGTCTCTGCCATACCAGAACATACATCCAGTGACTATTGGTGAATGTCCC AAGTACGTCCGGTCTGCCAAGCTGCGGATGGTGACTGGCTTGCGCAATAACCCTAGCATT CAGTCCAGAGGGCTGTTCGGCGCAATCGCCGGGTTCATCGAGGGGGGCTGGACTGGCATG ATCGATGGCTGGTATGGATATCACCATCAGAATGAACAGGGGAGCGGTTATGCGGCCGAT CAGAAATCGACCCAGAACGCAATCAATGGAATTACCAACAAGGTTAACACAGTCATAGAG AAAATGAACATCCAGTTCACGGCCGTTGGGAAGGAGTTTAATAAGTTGGAAAAGCGAATG GAAAACCTGAATAAAAAAGTCGACGACGGCTTCCTGGATATCTGGACCTATAACGCCGAG CTACTCGTTCTGTTGGAGAACGAGAGGACACTCGACTTCCATGACAGCAATGTGAAAAAC CTGTACGAAAAGGTGAAAAGTCAGCTCAAGAACAATGCAAAAGAGATCGGCAACGGATGT TTCGAGTTTTACCACAAGTGCGATAATGAGTGTATGGAAAGCGTGCGCAATGGCACTTAT GACTACCCCAAGTATTCTGAGGAGTCCAAATTGAATCGAGAAAAGGTGGATGGCGTCAAG CTAGAATCGATGGGGATATACCAGATATTGGCCATCTACTCCACCGTGGCCTCCTCCCTC GTCCTTCTTGTTTCGCTGGGCGCCATCTCTTTTTGGATGTGCTCAAACGGCTCGCTTCAG TGTCGCATTTGCATC 432 ATGAAGGCAAACCTGTTAGTTCTCCTCTGCGCTTTGGCTGCGGCCGACGCCGACACAATC TGTATCGGTTATCATGCGAACAACTCAACTGACACAGTGGATACTGTGCTGGAAAAAAAT GTGACAGTCACCCACTCTGTGAATCTGCTAGAGGACTCACACAACGGAAAGCTGTGCAGG CTCAAGGGCATTGCGCCACTGCAATTAGGAAAGTGTAACATCGCTGGATGGCTACTGGGA AACCCCGAGTGTGACCCCCTGCTTCCTGTGCGTAGTTGGAGTTATATCGTCGAAACTCCA AACAGCGAAAACGGCATTTGTTATCCCGGCGATTTCATCGATTATGAGGAATTGCGGGAG CAACTATCTAGCGTGTCTAGTTTTGAGAGATTCGAGATCTTCCCTAAAGAGTCTTCCTGG CCCAATCATAACACAAATGGTGTCACCGCAGCCTGCAGTCACGAGGGGAAGAGTAGCTTT TATCGCAACCTGCTGTGGCTGACCGAAAAGGAAGGCTCCTATCCTAAACTTAAGAACAGC TACGTGAACAAAAAGGGTAAGGAGGTCCTTGTTCTCTGGGGAATCCACCACCCCCCTAAT AGCAAAGAGCAGCAAAACCTTTATCAGAATGAGAACGCTTATGTTTCTGTGGTGACCTCA AACTATAATAGACGTTTCACACCTGAAATCGCCGAAAGGCCCAAGGTTCGAGATCAAGCC GGTCGTATGAATTACTATTGGACGCTGCTAAAGCCAGGCGACACCATAATTTTCGAAGCG AACGGTAACTTGATCGCCCCTATGTATGCATTCGCCCTGTCACGTGGCTTTGGCTCTGGT ATTATCACCAGCAATGCCTCTATGCACGAGTGTAATACTAAATGTCAGACCCCACTCGGC GCTATCAACTCATCCTTGCCCTACCAGAACATACATCCAGTGACAATTGGAGAATGCCCG AAATACGTGCGTAGTGCCAAGCTGAGAATGGTGACTGGTCTCCGGAATAACCCCTCTATA CAGTCCAGGGGCCTGTTTGGGGCTATTGCCGGTTTTATTGAGGGAGGTTGGACTGGCATG ATCGATGGATGGTACGGCTATCACCACCAGAACGAGCAAGGCTCTGGCTATGCCGCAGAC CAGAAATCAACACAAAACGCTATCAATGGAATAACTAACAAGGTCAACACAGTGATTGAA AAAATGAACATCCAGTTTACGGCTGTGGGCAAGGAGTTCAACAAGCTGGAAAAGAGGATG GAAAATCTCAACAAAAAAGTCGACGACGGCTTCTTGGACATCTGGACTTACAATGCAGAG TTGCTTGTTCTGCTGGAAAACGAACGTACGCTGGACTTCCACGACAGTAATGTCAAGAAT TTGTATGAAAAAGTGAAATCACAGCTGAAAAATAATGCGAAGGAGATAGGCAATGGCTGT TTTGAGTTCTATCATAAGTGCGATAATGAGTGCATGGAGTCAGTGCGAAACGGGACCTAC GACTACCCCAAATATAGTGAAGAGAGCAAGCTGAATAGAGAGAAAGTCGATGGCGTTAAA CTTGAGAGCATGGGTATCTATCAAATCCTGGCTATTTACAGTACAGTGGCCTCCTCTCTA GTGCTGCTCGTATCTCTCGGAGCGATATCCTTCTGGATGTGTTCCAATGGCTCTCTACAG TGCCGGATATGCATA 433 ATGAAAGCTAATCTGCTTGTACTGCTGTGCGCACTGGCAGCCGCAGACGCTGACACTATC TGTATCGGGTACCACGCCAACAATTCGACCGATACTGTGGACACAGTGTTGGAGAAGAAC GTCACCGTAACGCACAGCGTGAACCTTTTAGAAGATAGTCATAATGGAAAGCTGTGTAGG CTCAAGGGAATCGCTCCACTTCAGTTGGGAAAATGCAATATCGCTGGCTGGCTACTGGGC AACCCTGAATGCGACCCCCTGCTGCCTGTGCGATCCTGGTCCTATATTGTAGAGACCCCC AACTCAGAGAATGGCATTTGCTACCCAGGCGATTTTATTGACTACGAGGAGCTGAGAGAG CAGTTGTCCTCCGTCTCCAGCTTTGAAAGGTTTGAGATTTTCCCAAAAGAGTCCAGCTGG CCAAATCACAATACAAATGGTGTGACCGCCGCTTGTTCTCACGAAGGCAAAAGCTCCTTC TATAGAAATCTTCTGTGGCTAACAGAAAAAGAAGGATCATACCCAAAGTTGAAAAACAGC TACGTTAATAAGAAAGGCAAAGAGGTGCTGGTCCTGTGGGGTATCCACCACCCACCCAAT TCTAAAGAACAACAAAATTTGTACCAAAATGAAAACGCCTACGTTTCTGTCGTCACTAGC AATTATAACCGGAGGTTCACACCCGAGATCGCAGAAAGACCTAAGGTGAGAGACCAAGCC GGCAGAATGAATTATTACTGGACTCTCCTCAAACCCGGGGACACCATCATCTTCGAAGCT AACGGCAATCTGATTGCTCCTATGTACGCTTTTGCTCTGTCCCGGGGGTTTGGCAGCGGT ATTATCACATCAAACGCCAGTATGCACGAGTGTAATACGAAATGCCAGACTCCTCTGGGG GCTATCAATTCCAGTCTGCCCTATCAGAATATTCATCCTGTCACGATCGGTGAGTGCCCT AAGTATGTGCGAAGCGCCAAACTGCGGATGGTAACGGGCCTGAGGAATAACCCCTCTATT CAGTCTCGCGGGCTGTTTGGCGCAATCGCCGGCTTTATCGAGGGCGGTTGGACTGGCATG ATCGACGGATGGTACGGGTACCATCACCAGAACGAACAGGGGTCCGGCTACGCCGCCGAC CAGAAATCAACCCAGAACGCGATTAACGGGATCACCAACAAGGTGAATACTGTGATTGAG AAGATGAATATTCAGTTTACAGCAGTGGGCAAGGAGTTTAACAAACTTGAGAAACGCATG GAGAATCTCAACAAAAAGGTTGACGATGGATTCCTTGATATTTGGACATATAATGCCGAG CTGCTGGTCCTTCTGGAAAATGAACGCACACTGGATTTTCACGACTCGAACGTGAAGAAT CTGTACGAGAAGGTAAAGTCCCAATTAAAAAACAATGCTAAGGAGATAGGCAACGGCTGC TTCGAGTTTTACCACAAGTGCGATAACGAGTGCATGGAGTCTGTGAGAAACGGTACGTAC GATTACCCCAAATATTCCGAAGAGAGCAAGCTCAACCGCGAGAAAGTAGACGGCGTTAAA CTGGAGAGCATGGGCATCTACCAGATCCTCGCCATTTACTCCACTGTGGCCTCGTCACTA GTTCTCTTGGTGTCCCTGGGAGCCATCTCATTTTGGATGTGCTCCAACGGCTCACTACAG TGCCGGATTTGTATC 434 ATGAAGGCCAACCTCCTGGTGTTACTTTGTGCCCTAGCAGCCGCAGACGCCGACACTATC TGCATCGGATACCATGCTAATAACAGCACCGATACAGTAGATACCGTTTTGGAAAAGAAT GTCACTGTCACCCACAGCGTTAATCTGTTGGAGGATAGCCACAACGGTAAACTGTGCAGG CTGAAGGGAATTGCCCCCCTTCAACTGGGCAAGTGCAACATTGCAGGCTGGCTCCTCGGT AACCCTGAGTGCGATCCTTTACTCCCTGTTAGAAGCTGGAGCTACATCGTGGAGACCCCC AATAGTGAGAACGGAATCTGCTACCCTGGAGATTTCATCGACTATGAAGAACTTCGGGAA CAGCTCAGTTCAGTGTCGAGCTTCGAGAGATTCGAGATCTTTCCAAAGGAGTCCAGCTGG CCTAATCACAACACAAATGGCGTTACAGCAGCATGCTCACACGAAGGCAAGAGCAGCTTC TACCGCAACCTGCTGTGGCTTACCGAGAAGGAGGGATCCTATCCCAAGCTCAAGAATTCT TATGTGAATAAAAAGGGTAAGGAAGTGCTGGTCCTGTGGGGTATCCATCATCCGCCAAAT TCTAAGGAACAGCAGAATCTGTATCAGAATGAAAATGCCTACGTGAGTGTTGTGACTTCG AATTACAACAGGCGGTTTACCCCGGAGATTGCTGAGCGGCCCAAAGTCCGGGATCAGGCT GGCCGCATGAATTATTATTGGACTCTGCTCAAGCCTGGCGACACCATCATTTTTGAGGCC AATGGCAACCTTATCGCTCCCATGTACGCCTTCGCCCTCAGTAGGGGATTCGGGTCTGGT ATCATCACTTCAAACGCCAGCATGCACGAGTGCAATACCAAGTGCCAGACACCACTCGGT GCCATTAATAGCTCTCTTCCATATCAGAATATACATCCAGTCACGATCGGGGAATGCCCC AAATATGTAAGAAGTGCCAAACTGCGCATGGTGACAGGCCTGCGGAACAACCCAAGCATC CAAAGCAGAGGGCTGTTTGGCGCCATCGCGGGCTTCATTGAAGGTGGTTGGACTGGCATG ATTGATGGCTGGTACGGATATCATCATCAGAACGAGCAGGGATCAGGGTACGCGGCCGAT CAGAAGAGTACCCAGAATGCCATTAACGGCATCACGAATAAAGTAAATACTGTCATCGAA AAGATGAACATCCAATTTACTGCTGTCGGGAAGGAGTTCAACAAACTGGAAAAAAGGATG GAGAACCTGAATAAGAAAGTTGACGACGGCTTTTTAGATATTTGGACGTATAACGCAGAA CTGCTCGTGCTCCTGGAGAACGAGAGGACCCTGGACTTTCACGACTCCAATGTGAAGAAC CTTTATGAGAAAGTCAAATCTCAGCTCAAAAACAACGCTAAAGAAATTGGGAATGGTTGT TTTGAGTTTTATCACAAATGCGACAACGAATGCATGGAGAGCGTCAGGAACGGGACATAC GACTATCCAAAGTACTCAGAAGAGTCAAAACTCAACAGAGAGAAGGTTGACGGAGTCAAA CTTGAGTCTATGGGCATATACCAGATCTTGGCGATCTATTCCACGGTGGCCTCAAGCCTT GTTCTGTTGGTCTCATTGGGTGCCATCAGCTTTTGGATGTGTAGTAACGGCAGTCTGCAG TGTAGAATTTGCATC 435 ATGAAAGCAAACCTGCTCGTGCTCCTGTGCGCTCTGGCAGCCGCAGATGCCGACACTATT TGCATCGGTTACCATGCCAACAACAGCACTGATACGGTGGATACCGTACTAGAGAAGAAT GTCACCGTAACCCACTCAGTGAACCTGCTCGAAGACTCTCACAACGGTAAGCTGTGTAGA TTAAAGGGAATTGCCCCCTTGCAGTTAGGAAAGTGTAACATAGCAGGTTGGCTCCTTGGC AATCCTGAGTGTGACCCCCTACTGCCAGTCCGCAGCTGGAGCTATATCGTTGAGACTCCC AACTCTGAAAATGGAATCTGTTATCCAGGTGACTTCATCGATTATGAAGAATTACGCGAG CAGTTGTCCAGTGTTAGCTCTTTCGAGAGATTTGAAATATTCCCAAAGGAGTCGTCCTGG CCCAATCACAACACCAATGGAGTGACCGCTGCTTGCTCCCACGAAGGGAAGAGCTCTTTC TATCGGAATCTGTTGTGGCTGACAGAAAAGGAGGGCAGCTATCCTAAACTAAAGAACAGC TACGTGAACAAGAAGGGAAAGGAGGTGCTCGTGCTGTGGGGCATTCATCATCCTCCAAAT TCCAAGGAGCAGCAGAACTTATATCAGAATGAGAATGCTTATGTCTCAGTGGTGACGTCA AATTACAACAGGCGCTTCACACCCGAGATCGCTGAGCGGCCCAAGGTCCGCGACCAGGCT GGTAGAATGAATTACTATTGGACCCTCCTGAAGCCCGGAGATACTATTATCTTCGAAGCA AATGGAAATTTGATCGCACCCATGTATGCTTTCGCTCTGTCCAGGGGATTCGGTAGTGGC ATTATCACCAGCAATGCAAGTATGCATGAGTGCAACACAAAATGTCAGACGCCGTTAGGG GCTATTAACAGCAGCCTCCCTTATCAGAACATTCATCCGGTTACCATCGGGGAGTGCCCT AAGTACGTGAGAAGTGCCAAACTGAGGATGGTGACAGGCCTGCGCAATAATCCCAGTATC CAGAGCCGAGGTCTCTTTGGTGCCATTGCGGGCTTTATTGAAGGGGGCTGGACCGGCATG ATCGACGGTTGGTACGGATACCACCACCAGAACGAACAGGGCAGTGGCTACGCCGCCGAC CAGAAGAGTACTCAGAACGCAATCAATGGAATTACGAACAAAGTTAATACCGTAATCGAA AAAATGAATATCCAGTTTACCGCCGTAGGCAAGGAGTTTAACAAGCTCGAAAAACGCATG GAAAACCTGAATAAGAAAGTGGATGATGGATTCCTTGACATCTGGACCTACAACGCGGAA CTTCTTGTCCTGCTCGAAAATGAGAGAACGCTCGACTTTCACGACAGCAATGTCAAGAAT CTGTACGAAAAGGTAAAGTCACAGCTGAAGAACAACGCTAAGGAGATAGGCAACGGCTGC TTCGAGTTTTACCATAAATGCGACAATGAATGCATGGAATCCGTGAGAAACGGCACTTAC GATTACCCCAAATACAGCGAAGAATCAAAGCTAAACAGGGAGAAGGTGGACGGGGTGAAA CTAGAAAGCATGGGCATCTATCAGATCCTCGCCATTTACTCCACAGTCGCATCTTCTTTA GTGCTCCTTGTGTCACTGGGCGCTATCTCGTTTTGGATGTGCTCAAACGGATCTCTGCAG TGTCGGATCTGTATT 436 ATGAAAGCAAATCTGCTAGTGCTGCTGTGCGCCCTGGCCGCCGCAGATGCAGATACTATC TGCATTGGTTACCATGCCAACAACTCTACCGATACCGTGGATACTGTCCTCGAGAAGAAT GTGACTGTGACTCATTCCGTGAACTTACTCGAAGACAGCCACAACGGAAAGCTGTGCCGA TTGAAGGGCATCGCGCCACTCCAGCTGGGGAAATGCAACATCGCCGGCTGGCTTTTGGGA AACCCCGAGTGCGATCCGCTATTGCCCGTAAGATCATGGTCCTACATCGTGGAAACACCA AATTCAGAAAATGGCATCTGCTACCCCGGAGATTTTATCGATTACGAGGAACTGAGGGAG CAACTGAGCAGCGTTAGTTCTTTTGAGCGATTCGAAATTTTCCCAAAGGAGTCCTCATGG CCCAATCACAATACCAATGGCGTTACAGCCGCTTGTAGCCATGAAGGTAAGAGTTCATTT TATCGAAATCTTCTCTGGCTGACGGAGAAGGAGGGTAGTTACCCTAAATTGAAAAATTCA TACGTGAACAAGAAAGGAAAGGAGGTGCTGGTCCTCTGGGGGATTCACCATCCCCCCAAT AGCAAAGAGCAACAGAATCTGTACCAGAACGAAAACGCTTATGTCTCCGTGGTCACCTCA AATTACAATAGACGGTTTACCCCGGAGATAGCCGAGAGGCCCAAAGTCCGCGATCAGGCC GGCCGCATGAACTACTACTGGACCCTCCTCAAGCCAGGGGATACCATCATATTCGAGGCG AATGGGAACTTGATTGCCCCGATGTACGCATTTGCTTTGTCCAGAGGCTTTGGCTCCGGG ATCATCACATCTAATGCCTCCATGCATGAATGCAACACAAAATGCCAGACACCCCTGGGC GCTATTAACTCCTCTCTACCTTACCAGAACATCCACCCGGTTACTATTGGCGAGTGTCCT AAATATGTCCGCAGCGCCAAACTGAGGATGGTGACAGGGCTGAGGAATAACCCCAGCATT CAGTCCAGAGGCTTGTTCGGCGCTATAGCGGGGTTCATAGAAGGAGGCTGGACCGGAATG ATCGATGGCTGGTACGGCTACCACCATCAGAACGAGCAGGGCTCCGGGTACGCCGCTGAC CAGAAGAGTACGCAGAACGCCATTAATGGAATCACCAACAAGGTGAATACCGTAATCGAG AAAATGAATATTCAGTTCACAGCTGTGGGGAAGGAATTCAATAAGCTGGAAAAACGCATG GAGAACCTGAATAAAAAAGTGGATGATGGCTTCTTGGATATCTGGACCTATAATGCGGAA CTCCTGGTCCTTTTGGAAAATGAGCGCACACTTGACTTTCATGACTCAAACGTTAAAAAC CTGTACGAAAAAGTCAAGTCACAGCTAAAGAATAATGCAAAGGAGATTGGCAACGGGTGC TTCGAATTTTATCATAAATGCGACAACGAATGCATGGAAAGCGTAAGGAATGGTACATAC GATTATCCTAAGTACAGTGAGGAGTCAAAGTTGAATCGCGAAAAAGTTGACGGTGTCAAA CTGGAATCCATGGGGATTTATCAGATTCTTGCAATTTACTCAACGGTGGCTAGTTCTCTG GTGCTGCTGGTCTCCCTGGGCGCAATTAGTTTCTGGATGTGTAGCAACGGCTCTCTCCAG TGCCGGATCTGTATT 437 ATGAAAGCAAATCTTCTGGTCCTGCTGTGTGCACTAGCCGCCGCCGACGCAGACACAATT TGCATCGGATATCACGCCAACAACTCTACGGATACAGTGGACACAGTGCTGGAGAAGAAC GTAACTGTTACACACAGCGTGAACCTGCTAGAAGATTCTCACAATGGCAAACTGTGCAGA CTGAAAGGAATTGCACCCTTGCAGTTGGGAAAATGTAATATCGCGGGTTGGCTCCTCGGT AATCCCGAATGCGACCCCCTACTTCCCGTCCGTTCTTGGTCTTACATAGTGGAGACACCC AACTCGGAGAATGGGATTTGCTATCCTGGGGATTTTATTGACTACGAGGAGCTCAGGGAA CAGTTGAGTTCTGTGTCATCATTCGAGAGGTTTGAAATCTTTCCCAAAGAGTCTTCTTGG CCTAATCACAACACTAACGGTGTGACCGCTGCTTGTTCTCACGAAGGCAAATCATCCTTC TACAGAAATCTGCTCTGGCTGACGGAGAAGGAAGGATCATACCCAAAGCTAAAGAATTCA TATGTGAATAAAAAGGGGAAGGAGGTCCTCGTTCTGTGGGGTATTCACCATCCCCCTAAT TCTAAAGAACAGCAGAACCTTTATCAGAATGAAAATGCATACGTGTCAGTGGTGACAAGC AACTATAACAGGCGCTTTACCCCGGAAATCGCCGAACGCCCGAAGGTGAGGGACCAGGCC GGGAGGATGAACTACTACTGGACCTTGCTGAAGCCGGGCGACACAATCATTTTTGAAGCT AACGGGAATCTAATTGCTCCCATGTACGCCTTTGCTCTGTCTCGCGGCTTTGGCAGCGGG ATTATCACTAGCAACGCGTCCATGCACGAGTGTAATACTAAATGCCAGACGCCACTGGGC GCAATCAATAGCAGCCTTCCATACCAGAACATACATCCCGTCACCATAGGAGAATGTCCA AAGTACGTCCGGTCTGCAAAACTAAGGATGGTGACCGGGCTTAGAAACAACCCAAGTATT CAGAGCCGGGGGCTCTTTGGTGCCATCGCAGGCTTTATCGAGGGAGGGTGGACAGGCATG ATAGACGGATGGTATGGATACCATCACCAGAATGAGCAGGGCAGCGGATACGCTGCCGAC CAAAAAAGCACCCAAAACGCTATCAATGGCATTACTAATAAGGTGAACACTGTGATTGAG AAGATGAACATTCAGTTCACCGCAGTCGGGAAGGAATTTAACAAGCTGGAGAAAAGGATG GAGAACTTAAACAAGAAGGTTGATGACGGGTTTCTCGACATATGGACGTATAACGCGGAG TTGCTGGTATTACTGGAGAATGAACGGACTCTTGACTTCCACGATTCAAATGTGAAGAAT CTCTATGAAAAAGTCAAATCGCAGCTCAAAAATAATGCCAAGGAGATCGGCAACGGCTGT TTCGAGTTTTATCACAAATGCGACAACGAATGTATGGAATCAGTGCGAAATGGCACATAT GACTATCCGAAATACTCCGAGGAAAGTAAGCTGAATAGAGAAAAGGTGGACGGAGTAAAG CTCGAGTCCATGGGGATCTACCAGATTTTGGCTATCTATTCCACAGTTGCTTCATCTCTG GTGCTGCTGGTTTCCTTAGGCGCCATATCGTTCTGGATGTGCTCCAACGGGTCCCTGCAG TGTCGAATCTGCATC 438 ATGAAGGCGAATCTACTTGTCCTGCTGTGCGCGCTTGCGGCTGCTGACGCCGACACGATC TGCATAGGCTACCATGCAAATAACTCCACTGACACCGTCGACACCGTTCTTGAGAAGAAT GTGACGGTTACTCACTCCGTGAACCTCTTAGAGGATAGTCACAATGGCAAGTTGTGCAGA TTAAAAGGCATAGCTCCTCTTCAGCTGGGGAAATGTAATATCGCCGGGTGGCTCCTCGGG AACCCTGAATGCGATCCTCTGCTACCTGTGAGGAGTTGGAGCTACATAGTCGAAACTCCT AACTCGGAGAATGGAATTTGTTACCCTGGAGACTTCATTGATTACGAAGAGCTGCGGGAA CAATTGTCCTCTGTGTCATCATTTGAGCGGTTTGAGATTTTCCCCAAAGAAAGTAGTTGG CCAAATCATAACACTAACGGGGTCACCGCCGCATGTTCCCATGAAGGAAAGAGCTCTTTT TATCGAAACCTCCTCTGGCTTACTGAGAAGGAAGGATCCTATCCCAAGCTCAAGAACTCC TACGTGAATAAAAAGGGCAAAGAAGTTCTGGTGCTGTGGGGTATTCACCATCCCCCCAAC TCAAAAGAGCAACAGAACCTCTACCAGAATGAGAATGCGTACGTGTCAGTGGTTACTAGC AACTACAATAGGCGGTTTACACCGGAGATCGCCGAGCGTCCTAAAGTGAGAGACCAGGCT GGAAGAATGAACTATTATTGGACGCTGCTCAAACCCGGTGACACTATCATTTTCGAGGCT AATGGGAACTTGATTGCCCCTATGTATGCTTTCGCCTTATCACGCGGATTTGGCTCCGGG ATCATTACCTCAAATGCCTCAATGCACGAGTGTAACACCAAGTGTCAGACACCCCTGGGC GCGATTAACAGCAGTCTGCCGTACCAAAATATCCACCCCGTGACGATTGGGGAGTGCCCT AAGTACGTGCGGAGTGCCAAACTGCGTATGGTGACAGGGCTGCGCAACAATCCTTCCATT CAGTCGAGAGGCCTGTTTGGCGCCATCGCCGGGTTCATCGAAGGGGGGTGGACCGGAATG ATTGATGGATGGTATGGGTACCATCATCAGAATGAGCAGGGGTCTGGATATGCAGCAGAC CAGAAATCGACTCAAAATGCAATAAATGGCATAACGAATAAAGTTAATACAGTGATAGAG AAGATGAATATCCAGTTTACTGCCGTGGGCAAGGAGTTCAATAAACTCGAGAAGCGCATG GAGAACCTTAACAAAAAGGTGGACGATGGATTCCTGGATATCTGGACTTATAATGCCGAG CTGCTGGTACTTCTCGAAAATGAGCGTACACTAGACTTCCATGACTCAAATGTAAAAAAT TTATATGAGAAGGTGAAATCCCAGCTCAAGAACAATGCAAAGGAGATCGGCAATGGGTGT TTCGAATTTTATCACAAGTGTGACAACGAGTGCATGGAATCAGTGAGAAACGGAACATAC GACTACCCTAAATATAGTGAAGAGTCTAAGCTGAATCGTGAGAAAGTGGACGGGGTGAAA CTCGAGTCTATGGGCATTTACCAGATTCTGGCTATTTATAGTACAGTGGCTTCAAGCTTA GTCCTTCTAGTGAGCTTGGGTGCCATTTCATTTTGGATGTGTAGTAATGGGTCATTGCAG TGTAGGATTTGTATC 439 ATGAAAGCAAACCTGCTGGTCTTATTGTGCGCCTTGGCAGCTGCCGATGCCGACACCATC TGCATCGGGTACCACGCCAATAATAGTACTGACACCGTCGATACCGTGCTCGAAAAGAAC GTAACTGTGACTCACAGTGTGAACCTGCTGGAGGATAGCCATAACGGCAAACTCTGCCGA CTGAAAGGAATCGCTCCCTTGCAACTGGGCAAGTGCAACATAGCAGGGTGGTTACTGGGG AACCCCGAGTGCGACCCGCTGCTCCCTGTAAGATCTTGGAGCTATATCGTGGAAACACCT AACTCAGAAAATGGGATATGTTACCCAGGTGACTTTATCGATTACGAAGAATTGAGGGAA CAGCTGAGCAGCGTTAGTAGCTTTGAACGATTTGAGATCTTCCCAAAGGAGTCCTCTTGG CCTAATCACAACACAAATGGGGTGACCGCCGCTTGCTCTCATGAGGGTAAAAGTAGCTTT TACCGGAACTTACTATGGCTGACCGAGAAAGAAGGAAGCTACCCCAAACTGAAAAATTCG TACGTGAATAAAAAGGGGAAAGAGGTGTTAGTGCTCTGGGGGATACATCACCCTCCAAAT TCCAAGGAGCAGCAGAATCTGTACCAAAACGAGAACGCCTACGTTTCCGTGGTGACTAGC AATTATAACAGGCGGTTTACACCTGAAATCGCCGAACGGCCTAAAGTTCGAGATCAGGCC GGGCGGATGAACTACTATTGGACTTTGCTCAAGCCTGGCGACACAATCATTTTTGAAGCC AACGGGAACCTGATCGCACCGATGTATGCTTTTGCACTGAGTCGGGGGTTTGGCTCTGGC ATTATCACCTCTAATGCGTCCATGCACGAATGTAATACCAAGTGTCAGACACCCCTGGGG GCTATAAACTCCTCCCTCCCCTATCAGAACATCCACCCTGTGACCATCGGAGAATGTCCT AAATATGTCCGCTCCGCCAAACTGCGGATGGTTACTGGCCTCAGAAATAATCCAAGCATT CAGAGTCGAGGCCTCTTCGGCGCGATCGCCGGCTTCATTGAGGGTGGCTGGACCGGCATG ATCGATGGGTGGTACGGGTATCATCATCAGAATGAACAGGGATCCGGCTACGCAGCAGAT CAAAAAAGCACACAGAACGCGATTAATGGCATTACTAACAAGGTGAACACGGTGATCGAG AAGATGAATATACAATTCACTGCTGTCGGGAAAGAGTTCAATAAGCTCGAAAAGAGGATG GAGAATTTGAACAAGAAAGTGGATGATGGCTTCCTGGACATTTGGACCTACAATGCTGAA CTCCTGGTCCTTCTGGAAAACGAAAGAACCCTAGATTTCCATGACTCTAACGTGAAGAAC CTTTACGAAAAGGTGAAGAGCCAGTTGAAAAACAACGCAAAGGAAATTGGAAATGGGTGC TTCGAGTTTTATCATAAGTGCGACAACGAGTGCATGGAAAGTGTCCGTAATGGCACTTAC GATTACCCCAAATATTCTGAAGAATCCAAGCTGAACAGGGAGAAAGTCGATGGGGTTAAA TTAGAATCCATGGGCATCTATCAGATACTGGCCATTTATTCCACTGTGGCGAGCTCCTTA GTGCTCTTGGTCTCTTTAGGTGCCATCTCCTTTTGGATGTGCAGTAACGGGTCCCTCCAA TGCAGGATTTGTATC 440 ATGAAGGCCAACCTCCTCGTTCTGCTGTGTGCGCTGGCAGCGGCAGATGCCGATACCATT TGTATCGGTTACCATGCCAACAATTCCACCGACACCGTCGACACTGTTCTTGAAAAGAAT GTAACTGTCACCCATTCTGTCAACTTGCTTGAAGATAGTCACAACGGCAAACTGTGTCGG CTTAAAGGCATAGCCCCGCTGCAACTGGGCAAATGTAACATCGCCGGATGGCTGCTGGGA AATCCAGAATGCGACCCCCTGTTGCCTGTGCGGTCTTGGAGTTACATAGTAGAAACCCCC AATTCCGAAAATGGGATTTGTTATCCTGGCGACTTCATCGATTATGAGGAGTTGAGAGAG CAATTGAGTAGCGTTTCTTCATTTGAGCGCTTCGAAATATTCCCGAAAGAGAGTTCATGG CCTAACCACAACACAAATGGAGTGACAGCTGCCTGTTCCCACGAAGGAAAAAGCTCCTTT TACCGTAACCTGCTATGGCTGACTGAAAAGGAGGGGTCCTACCCCAAACTTAAGAACTCT TATGTCAACAAGAAGGGGAAAGAGGTACTGGTTCTGTGGGGAATTCATCATCCCCCGAAT TCAAAAGAGCAGCAAAATCTGTACCAAAATGAAAACGCGTACGTCTCCGTTGTGACATCT AACTACAATAGGCGGTTCACGCCCGAGATCGCTGAACGGCCGAAAGTCCGGGACCAAGCT GGCAGAATGAACTATTACTGGACACTGCTCAAACCCGGCGACACCATTATTTTCGAGGCA AATGGGAACCTGATTGCACCAATGTACGCCTTCGCTCTGTCCAGGGGCTTTGGTAGCGGA ATTATCACCTCGAATGCTTCAATGCATGAGTGCAACACCAAGTGCCAGACACCTTTGGGC GCCATCAATAGTAGCCTTCCTTACCAGAACATTCACCCTGTCACCATTGGTGAATGTCCT AAGTACGTGCGAAGCGCCAAACTGCGGATGGTTACTGGCCTGCGAAATAATCCCTCCATC CAGTCTCGCGGTCTGTTCGGAGCCATTGCAGGGTTCATCGAGGGAGGCTGGACCGGGATG ATTGACGGCTGGTATGGGTACCACCATCAGAACGAGCAAGGATCCGGGTATGCCGCCGAC CAGAAGAGCACCCAGAACGCTATCAATGGGATTACAAATAAAGTCAACACCGTCATCGAG AAGATGAACATCCAATTCACTGCGGTTGGCAAGGAGTTCAACAAACTCGAGAAAAGAATG GAAAACTTGAATAAGAAGGTAGACGACGGGTTTCTGGATATCTGGACTTATAACGCCGAA TTATTGGTGCTGCTGGAGAATGAACGGACTTTAGATTTCCACGACTCCAATGTGAAGAAT CTATACGAGAAAGTGAAGTCTCAGTTGAAGAACAACGCCAAGGAGATAGGAAATGGCTGT TTCGAGTTTTATCACAAGTGCGATAATGAGTGCATGGAAAGCGTGCGCAACGGGACATAT GATTACCCGAAGTACTCCGAGGAAAGCAAACTAAATCGCGAAAAGGTAGATGGCGTGAAG CTGGAATCGATGGGAATCTACCAGATCCTAGCTATTTACTCTACTGTTGCCAGCTCTCTG GTGCTTCTGGTATCTCTGGGGGCCATTAGTTTCTGGATGTGCAGTAACGGCTCATTACAG TGTAGGATATGCATT 441 ATGAAAGCAAACTTGCTGGTTCTGTTGTGCGCTCTCGCGGCCGCTGACGCGGACACTATC TGCATCGGGTACCACGCGAATAATTCGACTGACACAGTTGACACTGTGCTCGAAAAGAAT GTGACCGTCACGCACTCCGTCAATCTCCTGGAGGACTCACACAATGGCAAACTTTGTCGT TTGAAGGGCATCGCACCCCTCCAACTCGGGAAATGCAACATTGCAGGTTGGCTTTTAGGT AATCCTGAGTGTGATCCCCTGCTGCCTGTGCGCAGCTGGAGCTATATTGTCGAGACACCC AACTCCGAAAATGGAATCTGTTACCCAGGAGACTTCATTGACTATGAAGAATTAAGAGAG CAATTAAGCTCCGTGAGCTCCTTTGAGAGGTTTGAGATCTTCCCGAAGGAAAGCTCCTGG CCTAACCATAACACCAATGGAGTGACTGCCGCCTGCAGCCACGAAGGAAAGTCTTCCTTC TATAGAAACCTACTGTGGTTGACAGAGAAGGAAGGCTCCTATCCTAAATTGAAGAACTCA TATGTCAACAAGAAGGGGAAAGAGGTCCTCGTGCTGTGGGGAATCCATCATCCTCCTAAC TCTAAGGAGCAACAAAATTTATACCAGAACGAAAATGCATACGTTTCTGTGGTTACATCA AACTATAATAGGCGCTTCACACCTGAGATTGCTGAACGTCCCAAAGTGAGGGATCAAGCG GGGCGTATGAACTACTACTGGACACTGTTAAAACCGGGGGATACCATCATCTTTGAGGCG AACGGCAATCTTATTGCACCTATGTATGCTTTTGCCCTCTCGCGCGGTTTCGGCAGTGGA ATAATAACATCAAATGCCAGTATGCACGAGTGCAATACGAAGTGCCAGACTCCCTTAGGC GCTATAAATAGTTCCTTACCTTACCAGAATATTCACCCAGTGACCATCGGCGAATGCCCA AAGTACGTCAGGTCTGCGAAACTGAGAATGGTCACAGGGTTGAGAAATAATCCATCTATC CAGTCACGAGGCCTGTTTGGCGCGATCGCGGGCTTTATTGAAGGAGGGTGGACGGGTATG ATTGACGGATGGTACGGTTACCATCATCAAAATGAACAAGGTTCAGGGTATGCCGCGGAC CAGAAGAGCACCCAGAATGCAATCAATGGCATTACCAACAAGGTGAACACGGTGATCGAG AAGATGAATATTCAGTTTACCGCTGTGGGCAAGGAGTTTAATAAGCTCGAGAAACGCATG GAAAATCTGAACAAAAAAGTAGACGATGGATTCCTCGACATATGGACGTACAATGCCGAG CTTCTCGTCCTCTTAGAGAACGAGCGGACCCTGGATTTCCACGATTCAAACGTCAAAAAC CTGTATGAGAAAGTCAAGAGCCAGCTTAAGAATAACGCCAAGGAAATCGGGAACGGCTGC TTCGAGTTCTATCATAAATGCGACAATGAGTGTATGGAATCTGTACGCAATGGAACATAC GACTACCCTAAGTACTCCGAAGAAAGCAAACTGAATAGGGAGAAGGTAGACGGAGTGAAA TTGGAGAGCATGGGCATATACCAGATCCTGGCCATTTACTCAACCGTCGCCTCATCCTTG GTGTTGCTGGTGTCCTTGGGTGCTATTTCTTTTTGGATGTGCAGCAATGGCAGTCTCCAG TGCAGGATTTGTATC 442 ATGAAGGCTAACCTGCTGGTGCTCCTCTGCGCTCTGGCAGCTGCAGACGCTGATACCATT TGCATTGGCTACCATGCCAATAACAGCACCGATACAGTCGATACAGTTCTGGAGAAGAAC GTGACAGTGACTCACAGCGTTAATCTGTTGGAGGACAGCCATAATGGGAAGCTGTGTCGC CTGAAGGGAATTGCTCCATTACAGCTGGGGAAATGTAACATCGCTGGATGGCTGTTGGGA AACCCAGAGTGTGATCCCCTACTTCCTGTACGGAGTTGGAGTTATATCGTGGAGACACCC AATAGTGAGAACGGTATCTGTTATCCTGGAGATTTTATAGACTATGAAGAGTTAAGGGAG CAGCTGAGCTCCGTCAGTTCATTCGAACGCTTCGAAATTTTCCCTAAGGAGTCTTCCTGG CCCAACCACAATACCAACGGGGTCACCGCTGCTTGTAGTCATGAAGGAAAATCTAGCTTC TACCGAAACCTGCTCTGGCTAACTGAGAAAGAAGGATCATACCCGAAGCTGAAGAATAGC TACGTGAACAAGAAGGGGAAGGAAGTGCTGGTTCTGTGGGGCATTCACCACCCCCCTAAC AGTAAGGAACAGCAGAACCTCTATCAGAATGAGAACGCATACGTGAGTGTCGTTACAAGC AACTACAATCGCCGGTTTACTCCAGAGATCGCGGAAAGACCCAAAGTCAGGGACCAGGCT GGTAGGATGAATTACTATTGGACCCTTCTCAAACCTGGGGACACTATCATATTCGAGGCC AATGGCAACCTGATTGCCCCTATGTACGCCTTTGCTCTGAGCCGCGGATTCGGCTCCGGC ATAATCACGTCTAATGCTTCCATGCACGAGTGTAACACAAAATGTCAGACGCCCTTGGGC GCTATCAATTCTAGTCTGCCTTATCAGAACATACATCCAGTCACTATCGGAGAGTGCCCA AAGTACGTTCGCTCTGCAAAGCTCCGGATGGTTACAGGTCTAAGAAATAATCCTAGTATT CAGAGCAGGGGCCTGTTTGGAGCCATAGCTGGATTTATAGAGGGCGGATGGACTGGGATG ATAGATGGGTGGTATGGCTACCATCACCAGAATGAACAGGGGAGCGGATACGCTGCCGAC CAAAAATCTACTCAGAACGCAATTAATGGTATCACAAACAAAGTGAACACAGTGATCGAA AAGATGAACATTCAGTTCACTGCTGTGGGGAAAGAGTTCAACAAGCTGGAGAAACGAATG GAAAATCTGAATAAAAAGGTGGACGACGGATTCCTTGACATTTGGACTTACAACGCCGAA TTACTTGTCCTCTTGGAAAACGAACGGACCCTGGATTTTCATGACTCCAATGTTAAGAAC CTGTATGAGAAGGTGAAGAGCCAGCTGAAAAATAACGCAAAGGAAATCGGGAACGGATGT TTTGAGTTTTACCACAAGTGCGATAATGAATGTATGGAGAGTGTTCGGAATGGGACATAC GACTACCCTAAGTATTCTGAGGAGTCTAAGCTCAACCGGGAGAAGGTGGATGGTGTTAAG TTAGAGAGTATGGGAATTTACCAGATTCTGGCCATATACTCTACAGTAGCATCTTCTCTG GTGTTATTGGTCAGTCTCGGTGCTATTTCTTTTTGGATGTGCTCAAACGGCTCACTGCAG TGCCGCATCTGTATC 443 ATGAAAGCAAACCTGCTGGTCCTCTTGTGCGCGCTGGCAGCCGCCGATGCTGACACCATA TGTATTGGCTATCACGCTAACAATTCTACGGACACTGTGGATACGGTGCTGGAGAAAAAC GTAACCGTCACACACAGCGTGAATCTGCTGGAGGATTCGCATAATGGTAAACTTTGCAGA CTGAAGGGGATAGCCCCGCTCCAGTTGGGTAAGTGTAATATCGCCGGATGGTTGCTTGGG AACCCCGAGTGTGATCCTCTGTTGCCGGTGCGCAGTTGGTCGTACATCGTGGAAACCCCG AATAGTGAGAATGGCATTTGTTATCCAGGGGACTTCATCGATTACGAAGAGCTCAGGGAG CAGCTCAGCTCTGTAAGTAGCTTCGAACGGTTCGAGATCTTCCCCAAAGAAAGCTCCTGG CCCAATCACAACACTAACGGGGTGACAGCGGCCTGCAGCCACGAGGGCAAAAGTTCTTTC TATCGCAACCTACTGTGGCTCACCGAGAAGGAGGGAAGTTACCCTAAGCTGAAGAACAGC TATGTCAACAAGAAAGGCAAGGAGGTCCTTGTGTTATGGGGCATTCACCACCCTCCCAAT AGCAAAGAGCAGCAAAACCTTTATCAAAATGAGAACGCCTACGTGAGCGTGGTGACCTCT AACTACAACAGAAGGTTTACACCAGAGATCGCCGAAAGGCCTAAAGTTAGGGACCAGGCC GGACGGATGAATTACTATTGGACGTTATTAAAGCCTGGGGATACCATTATCTTTGAGGCC AATGGCAACTTGATCGCCCCTATGTACGCCTTTGCTCTCTCGCGCGGATTTGGTTCCGGA ATCATTACCAGCAATGCTTCAATGCATGAGTGCAATACAAAGTGTCAGACCCCACTGGGC GCTATTAACTCGTCTTTACCGTATCAAAATATACATCCCGTGACTATTGGTGAGTGCCCT AAATATGTTCGCTCTGCTAAGCTCAGGATGGTTACTGGACTGCGGAACAATCCGTCGATT CAGTCCAGGGGACTCTTCGGCGCAATTGCGGGTTTCATCGAGGGTGGCTGGACGGGCATG ATCGACGGCTGGTACGGTTACCACCATCAGAACGAACAGGGATCCGGCTACGCAGCCGAT CAAAAGTCTACGCAGAACGCTATTAATGGAATCACCAACAAGGTGAATACAGTTATCGAA AAGATGAATATACAGTTTACTGCCGTGGGGAAAGAATTCAACAAACTGGAGAAGAGAATG GAGAATCTTAACAAGAAGGTCGACGATGGCTTCCTTGATATCTGGACGTACAATGCCGAG CTGCTGGTCCTCCTCGAGAATGAACGAACTCTGGACTTCCACGACTCCAATGTAAAGAAT CTCTATGAAAAGGTGAAATCCCAGCTGAAAAATAACGCCAAGGAGATAGGAAATGGCTGC TTCGAATTTTACCACAAATGTGACAATGAATGCATGGAGTCCGTGAGAAATGGAACCTAC GACTATCCCAAATATTCAGAAGAGTCAAAGCTAAATCGCGAAAAAGTTGACGGAGTCAAG CTCGAGTCTATGGGCATATATCAGATTCTGGCCATCTACTCCACCGTGGCCTCTTCCCTT GTCCTTCTAGTGTCCTTGGGTGCAATTTCTTTTTGGATGTGCAGCAACGGGTCCCTGCAA TGCAGGATTTGTATA 444 ATGAAGGCCAACCTTCTCGTCTTACTATGTGCACTTGCCGCAGCAGATGCCGATACTATC TGCATCGGCTATCATGCCAATAACAGCACAGACACCGTGGATACGGTGCTGGAGAAGAAC GTTACAGTGACCCACTCCGTTAATCTGCTTGAAGATAGTCATAACGGCAAGCTGTGTCGC TTGAAAGGGATCGCCCCTCTCCAGCTGGGTAAGTGCAACATTGCTGGGTGGCTCCTTGGC AACCCTGAGTGTGACCCACTACTTCCTGTGAGAAGTTGGAGCTATATCGTAGAGACACCA AATTCTGAAAACGGAATCTGTTATCCCGGAGACTTCATCGACTACGAGGAACTGCGCGAA CAACTGTCTTCCGTCTCTTCCTTTGAGAGATTTGAGATCTTTCCCAAAGAAAGTAGTTGG CCAAACCATAATACTAACGGCGTGACAGCAGCCTGTAGTCACGAAGGCAAGTCCAGTTTT TACCGCAACCTGCTCTGGCTGACAGAAAAGGAGGGGAGTTATCCAAAGCTGAAAAACTCT TACGTCAACAAGAAAGGGAAAGAGGTCCTGGTTCTTTGGGGCATTCATCATCCCCCAAAT TCAAAGGAACAGCAGAATCTTTACCAGAACGAAAATGCTTACGTGAGTGTGGTCACCAGT AACTACAACAGGAGGTTCACACCAGAGATAGCAGAACGGCCAAAAGTAAGAGATCAGGCT GGTAGGATGAACTATTACTGGACACTGCTCAAGCCGGGTGACACCATAATCTTTGAGGCT AATGGCAACCTTATTGCTCCCATGTACGCTTTCGCTCTTAGCAGAGGGTTTGGCAGCGGC ATTATCACATCAAATGCAAGCATGCACGAGTGCAACACCAAGTGTCAAACACCCCTCGGC GCAATAAATAGCAGCTTGCCATATCAGAATATACACCCCGTGACAATCGGCGAGTGTCCT AAATACGTACGCTCTGCAAAACTCCGCATGGTGACCGGCCTCCGTAACAACCCCAGCATC CAGAGTCGGGGGCTCTTTGGCGCCATCGCCGGGTTTATTGAAGGGGGGTGGACAGGGATG ATTGATGGTTGGTATGGATATCACCACCAGAACGAACAAGGATCAGGTTACGCGGCGGAC CAGAAGAGCACCCAAAACGCTATAAACGGCATAACCAACAAGGTAAACACCGTTATTGAA AAGATGAATATTCAGTTTACCGCAGTCGGTAAAGAGTTTAATAAGCTCGAGAAGAGGATG GAAAATCTGAACAAGAAGGTTGATGATGGGTTTTTAGATATTTGGACCTACAATGCGGAG CTGCTCGTCCTGTTAGAAAATGAGAGGACACTGGACTTCCACGATAGTAATGTGAAGAAC CTCTATGAGAAGGTGAAAAGTCAGCTCAAGAATAACGCTAAAGAGATTGGGAATGGTTGT TTTGAATTTTATCACAAATGCGACAATGAATGTATGGAGAGTGTAAGGAACGGTACGTAC GACTACCCAAAATATTCAGAAGAGTCTAAACTCAATAGAGAGAAGGTTGACGGAGTGAAA CTGGAGTCCATGGGCATTTACCAGATCCTGGCAATCTACTCTACTGTTGCTAGCTCGTTG GTGTTGCTCGTCAGTCTGGGAGCTATCTCCTTCTGGATGTGTAGTAATGGGAGCCTGCAG TGCCGGATCTGTATT 445 ATGAAGGCTAATCTACTGGTTCTTCTGTGCGCGCTCGCCGCAGCAGATGCTGATACTATC TGCATCGGGTATCATGCTAATAACAGCACCGACACCGTCGATACGGTACTAGAGAAAAAC GTTACTGTGACTCACTCCGTGAACCTGCTGGAAGACTCACATAACGGCAAACTGTGTCGC CTGAAGGGGATTGCCCCCCTGCAGCTGGGGAAGTGTAATATAGCGGGATGGCTGTTGGGG AATCCTGAGTGTGATCCACTTCTCCCCGTGAGATCCTGGAGTTACATTGTGGAGACTCCA AATTCGGAGAACGGGATCTGCTATCCAGGAGACTTCATCGACTACGAAGAATTGCGAGAG CAACTGTCTAGCGTGTCCTCCTTTGAAAGATTCGAGATTTTTCCAAAGGAGTCCAGTTGG CCTAACCATAACACTAACGGCGTGACTGCCGCTTGTTCTCACGAGGGCAAGTCTTCTTTT TATAGAAACCTTCTCTGGCTCACCGAAAAAGAAGGTTCCTATCCCAAACTCAAAAACTCC TACGTGAATAAGAAAGGCAAAGAAGTCCTGGTGTTGTGGGGTATACACCATCCGCCTAAC TCCAAGGAACAGCAGAATCTCTACCAGAACGAGAATGCATACGTGTCAGTTGTCACCTCC AACTACAACCGGCGGTTCACCCCTGAGATCGCCGAAAGGCCAAAAGTGCGTGACCAGGCC GGACGCATGAACTACTACTGGACTCTCTTGAAGCCAGGAGACACCATTATCTTCGAAGCC AATGGCAACCTGATTGCCCCCATGTACGCTTTCGCACTCAGCAGAGGTTTCGGGTCCGGC ATAATTACTAGCAACGCCAGCATGCACGAATGCAACACTAAATGTCAGACCCCACTCGGA GCCATCAACTCCAGTCTGCCCTACCAGAATATTCACCCTGTCACCATCGGCGAATGCCCC AAGTACGTGAGGAGTGCTAAACTTCGAATGGTGACCGGCCTGCGGAACAATCCGAGCATT CAGTCCCGGGGATTGTTTGGAGCCATCGCTGGATTTATAGAGGGGGGCTGGACCGGCATG ATCGACGGCTGGTATGGCTATCATCATCAAAATGAACAGGGCAGCGGCTATGCAGCTGAC CAAAAGTCAACCCAGAACGCTATTAACGGAATCACAAACAAGGTGAATACCGTGATAGAA AAGATGAATATTCAGTTCACGGCTGTGGGAAAGGAATTCAACAAGTTAGAGAAGAGGATG GAAAATCTGAATAAGAAGGTGGACGACGGGTTCTTGGATATCTGGACATACAACGCTGAG CTCTTGGTGCTGCTCGAAAATGAACGGACTCTTGACTTTCACGACTCAAACGTAAAAAAT CTCTATGAAAAGGTGAAATCTCAGTTGAAGAATAACGCAAAGGAGATTGGCAATGGGTGC TTCGAATTCTATCACAAGTGTGATAACGAGTGTATGGAGTCAGTCCGGAATGGGACTTAC GACTATCCCAAGTATAGTGAAGAATCTAAGCTCAATCGCGAAAAGGTGGACGGGGTGAAG TTGGAATCAATGGGTATTTATCAGATCCTCGCAATTTACTCTACCGTGGCCTCCTCATTG GTTTTGCTGGTGTCCCTTGGAGCTATAAGCTTCTGGATGTGCAGTAATGGGTCACTACAG TGCCGTATTTGCATT 446 ATGAAGGCCAACTTGCTGGTGCTTCTTTGCGCCCTCGCAGCAGCTGACGCCGATACCATC TGTATAGGCTATCACGCAAACAATAGCACCGATACTGTGGATACCGTGCTTGAGAAGAAC GTTACAGTGACACATTCAGTGAACCTACTCGAGGACTCCCACAATGGAAAGCTGTGTAGG CTGAAAGGCATTGCACCACTGCAGCTCGGGAAATGTAATATAGCAGGGTGGCTCCTCGGC AATCCCGAGTGCGATCCCCTGCTGCCCGTCAGGTCATGGAGCTACATTGTAGAAACCCCG AACTCTGAGAATGGCATTTGTTATCCCGGAGATTTCATCGACTACGAAGAACTGCGAGAG CAACTCTCATCCGTGTCTTCATTTGAAAGGTTCGAGATCTTCCCCAAGGAGTCTAGCTGG CCTAATCACAACACAAACGGCGTGACTGCCGCCTGTTCACACGAGGGTAAGAGTTCATTT TACAGGAACCTCCTGTGGCTGACTGAGAAGGAAGGCAGCTATCCAAAGTTGAAGAATTCG TACGTGAACAAGAAGGGGAAAGAAGTTCTGGTACTCTGGGGGATCCACCACCCGCCTAAT TCCAAAGAACAGCAGAATCTATACCAGAACGAAAATGCTTACGTCAGCGTTGTGACATCC AATTACAACAGAAGATTTACCCCAGAGATAGCCGAGCGACCCAAGGTGAGGGACCAGGCG GGACGAATGAATTATTACTGGACCCTGTTGAAGCCAGGAGACACCATCATTTTTGAAGCC AACGGAAATCTTATCGCGCCGATGTACGCGTTCGCACTGTCACGAGGATTTGGCTCGGGG ATTATTACCTCAAATGCTAGCATGCACGAATGCAACACTAAGTGTCAGACTCCGCTGGGA GCTATCAATTCATCTCTCCCATATCAGAATATTCATCCCGTGACCATAGGCGAGTGCCCC AAATACGTCCGGTCGGCAAAATTGCGGATGGTTACTGGTCTGAGAAATAATCCATCCATA CAGTCTCGCGGTTTATTTGGGGCGATTGCAGGCTTTATTGAGGGGGGATGGACGGGCATG ATCGATGGTTGGTACGGATATCACCACCAAAACGAGCAAGGGAGTGGTTATGCCGCCGAT CAGAAGTCGACACAAAACGCAATAAATGGTATAACAAATAAAGTTAACACCGTAATCGAG AAGATGAACATCCAGTTTACAGCCGTGGGGAAGGAATTCAACAAGCTGGAAAAGCGCATG GAGAACCTGAACAAAAAGGTGGATGACGGCTTCCTGGACATTTGGACCTACAACGCAGAG TTGTTAGTGCTGCTGGAGAATGAGCGAACACTGGATTTTCATGACTCCAATGTGAAGAAT CTCTACGAGAAGGTGAAGTCACAGCTCAAGAACAATGCTAAAGAGATTGGGAACGGGTGC TTCGAATTTTACCATAAATGCGACAACGAGTGTATGGAGTCCGTCCGTAATGGCACTTAT GACTACCCTAAATACTCTGAAGAGTCCAAACTCAATCGGGAGAAAGTGGACGGTGTGAAG CTGGAGTCAATGGGGATATACCAGATCTTAGCAATTTACAGCACCGTCGCCTCCTCATTG GTGCTTCTGGTCTCTCTCGGAGCAATTAGTTTTTGGATGTGTTCCAATGGGTCTCTCCAG TGCCGGATATGCATT 447 ATGAAAGCCAACCTTCTAGTGTTACTTTGCGCTCTCGCCGCTGCCGATGCCGATACAATC TGTATCGGTTATCACGCGAATAATTCCACCGACACTGTCGATACAGTGTTGGAAAAGAAT GTCACAGTCACACATTCCGTCAATTTGTTGGAGGACAGCCATAACGGAAAGTTGTGTAGA TTGAAAGGGATTGCCCCACTGCAGCTGGGTAAGTGTAATATTGCTGGTTGGCTACTGGGC AACCCAGAATGTGACCCCCTTCTACCCGTCAGGAGTTGGAGCTACATTGTGGAGACCCCT AACAGCGAGAATGGCATTTGCTACCCAGGCGACTTTATCGATTACGAAGAACTGCGGGAA CAGTTGAGCTCTGTTAGTAGCTTCGAGAGATTCGAGATATTCCCAAAGGAGTCAAGCTGG CCCAATCACAACACCAATGGGGTTACAGCAGCTTGTAGCCATGAAGGCAAAAGCAGCTTC TATCGAAATCTACTCTGGCTCACCGAAAAGGAAGGATCCTACCCGAAACTCAAAAACAGC TACGTCAACAAGAAGGGAAAAGAGGTGCTGGTGCTGTGGGGAATCCATCATCCTCCCAAC AGCAAAGAGCAACAGAATTTGTATCAAAACGAAAACGCTTACGTGAGCGTGGTAACCTCA AACTATAACAGACGGTTTACACCAGAAATCGCAGAGAGGCCAAAAGTGCGGGACCAAGCC GGTAGAATGAACTATTACTGGACCCTCTTGAAACCTGGAGACACCATAATATTCGAGGCC AACGGAAATCTGATCGCCCCAATGTATGCCTTCGCTCTCTCTAGGGGCTTCGGCAGCGGG ATAATTACCTCCAACGCCAGCATGCATGAGTGCAATACCAAGTGTCAAACTCCCCTGGGC GCAATTAACAGCTCCCTGCCTTACCAAAACATTCACCCAGTCACCATCGGAGAGTGCCCC AAATACGTTAGATCTGCAAAGCTGCGGATGGTGACAGGTCTACGCAACAACCCCTCAATC CAGTCACGGGGGCTTTTCGGTGCCATTGCCGGGTTTATTGAAGGTGGCTGGACCGGCATG ATAGATGGGTGGTATGGCTACCACCATCAGAATGAACAGGGAAGTGGGTATGCAGCGGAC CAGAAAAGCACGCAGAACGCAATAAACGGGATCACGAATAAAGTGAACACCGTCATTGAA AAGATGAACATCCAGTTTACCGCGGTTGGAAAAGAATTTAACAAGCTCGAAAAAAGAATG GAAAATCTGAACAAGAAGGTCGACGACGGATTCCTTGATATTTGGACTTACAATGCTGAG CTTCTTGTACTGTTAGAAAACGAGCGAACCTTGGATTTCCACGATTCAAACGTCAAAAAC TTGTACGAGAAAGTGAAGAGCCAACTCAAGAACAACGCCAAGGAAATTGGGAATGGTTGC TTTGAATTTTACCATAAGTGCGACAATGAATGCATGGAGTCGGTACGAAACGGGACTTAT GATTATCCAAAGTATAGCGAAGAGAGTAAACTCAACCGGGAGAAAGTCGATGGGGTGAAA CTGGAGTCAATGGGAATTTATCAAATTCTGGCTATCTATTCTACAGTGGCCTCTTCTCTC GTCTTGCTAGTGAGCCTCGGAGCAATCTCTTTTTGGATGTGCAGCAATGGCTCCCTGCAA TGCCGCATCTGCATA 448 ATGAAGGCTAACCTCCTGGTGTTGTTGTGTGCCCTGGCTGCAGCTGACGCCGATACTATT TGCATAGGCTATCATGCTAATAATAGTACAGATACGGTTGACACCGTTCTCGAAAAGAAC GTGACGGTGACACATAGCGTTAATCTGCTAGAAGACTCCCACAATGGGAAGCTGTGCCGG CTGAAGGGGATCGCACCACTCCAGCTAGGTAAGTGCAATATCGCCGGGTGGCTGTTAGGA AATCCGGAGTGCGACCCTCTTCTCCCCGTGAGGTCTTGGTCCTACATCGTGGAAACTCCA AACAGTGAAAACGGAATCTGCTATCCTGGCGATTTTATAGACTATGAAGAGCTGCGTGAG CAACTGAGCAGCGTATCCAGCTTCGAAAGATTCGAGATTTTCCCTAAGGAATCGTCATGG CCGAATCACAACACTAATGGCGTCACTGCTGCATGCAGCCATGAGGGCAAAAGCAGCTTC TATAGAAATCTCCTGTGGCTTACCGAGAAAGAGGGTAGCTATCCTAAGCTCAAGAATAGC TATGTCAATAAGAAAGGCAAGGAGGTGCTGGTGTTGTGGGGAATCCATCACCCACCTAAC TCCAAAGAGCAGCAGAACCTGTATCAAAACGAGAACGCCTACGTGTCTGTAGTGACGAGC AACTACAACAGGCGTTTCACACCTGAGATCGCGGAGCGCCCCAAGGTTCGCGACCAAGCG GGGCGCATGAATTACTATTGGACTCTTTTAAAGCCGGGAGATACGATCATCTTTGAGGCT AACGGCAACTTAATCGCCCCTATGTACGCCTTTGCGTTGTCGCGGGGATTCGGATCCGGT ATAATAACAAGCAACGCAAGTATGCACGAATGTAATACTAAATGTCAAACCCCTTTAGGG GCCATTAACAGCAGCCTTCCGTACCAGAACATTCATCCCGTCACCATCGGCGAATGCCCA AAATATGTGCGGTCCGCGAAACTCAGAATGGTAACAGGCCTGCGGAATAATCCTAGTATA CAGTCCAGAGGACTTTTTGGGGCGATAGCTGGATTCATTGAAGGCGGATGGACTGGGATG ATTGACGGATGGTACGGCTACCACCATCAGAACGAACAGGGCAGTGGGTACGCTGCTGAT CAAAAATCCACACAAAATGCCATTAATGGAATTACAAACAAAGTTAATACAGTCATCGAG AAAATGAATATTCAGTTCACAGCTGTGGGCAAAGAGTTTAACAAACTGGAGAAACGAATG GAGAACCTGAACAAAAAGGTTGATGATGGCTTTCTGGACATCTGGACATATAATGCTGAG CTGTTGGTCCTACTGGAGAATGAGAGGACCTTGGACTTCCACGACTCCAATGTTAAGAAC CTATATGAGAAGGTTAAGTCGCAATTGAAAAACAATGCAAAGGAAATCGGGAACGGGTGC TTTGAATTCTATCATAAATGTGATAATGAGTGCATGGAAAGCGTGCGTAATGGGACTTAC GATTATCCTAAGTATAGTGAGGAATCTAAGTTGAACAGAGAGAAAGTGGATGGAGTCAAG TTAGAAAGTATGGGTATCTACCAAATTCTTGCTATATATAGCACAGTGGCTTCCAGCCTC GTCTTGCTTGTCTCTCTCGGGGCTATCAGCTTTTGGATGTGCTCAAACGGCAGCCTCCAG TGTCGGATATGTATC 449 ATGAAGGCTAACCTGCTGGTGCTGTTGTGTGCACTCGCAGCCGCGGACGCCGACACTATC TGCATAGGCTATCACGCTAATAACTCAACGGATACGGTGGATACCGTTCTGGAGAAGAAT GTAACCGTCACACACAGCGTCAATCTGCTCGAGGATAGCCACAACGGCAAACTATGCCGC CTGAAGGGGATAGCTCCCCTCCAGCTGGGAAAGTGTAACATTGCCGGATGGCTCCTGGGA AATCCAGAGTGCGATCCCCTGTTACCTGTCAGATCATGGTCTTACATCGTGGAGACCCCT AACTCCGAGAATGGGATCTGCTACCCCGGAGACTTTATTGACTACGAGGAGCTGAGAGAG CAATTGTCTTCAGTGAGTTCTTTTGAGAGGTTTGAAATCTTCCCGAAGGAGAGTTCATGG CCAAATCACAATACGAATGGAGTTACCGCAGCTTGCTCTCATGAGGGCAAGAGCAGTTTC TACAGGAACCTACTGTGGCTGACCGAGAAGGAAGGTAGCTACCCGAAGCTGAAGAATTCA TACGTCAATAAAAAGGGCAAGGAAGTGTTAGTGCTCTGGGGCATCCATCACCCCCCCAAC TCCAAAGAGCAGCAGAACCTTTATCAGAATGAAAACGCTTATGTTTCAGTGGTGACCTCT AATTATAACCGACGTTTTACTCCAGAGATCGCTGAAAGACCCAAGGTCCGTGACCAAGCA GGGCGGATGAACTATTACTGGACCCTGCTAAAGCCTGGCGATACTATAATTTTCGAAGCT AACGGCAACCTTATTGCTCCCATGTATGCATTCGCCCTGAGTCGTGGATTTGGCAGCGGT ATTATCACCTCTAATGCATCGATGCATGAATGTAATACAAAATGCCAGACTCCATTGGGC GCTATTAACTCAAGCCTTCCTTATCAAAATATCCACCCTGTAACTATCGGGGAGTGTCCC AAATATGTGCGCTCAGCCAAGCTCCGCATGGTAACTGGACTCCGCAACAATCCATCAATA CAGAGCAGAGGACTGTTCGGGGCGATAGCCGGGTTCATCGAAGGAGGCTGGACCGGCATG ATCGACGGGTGGTACGGTTACCATCACCAAAACGAGCAGGGCAGCGGCTACGCTGCCGAT CAAAAGTCCACACAAAATGCCATAAACGGAATAACCAATAAGGTCAACACTGTGATCGAA AAGATGAATATTCAGTTCACTGCTGTCGGTAAAGAATTCAATAAGCTGGAAAAGCGCATG GAGAACCTTAACAAAAAGGTGGACGACGGCTTTTTAGACATCTGGACCTACAATGCCGAA CTGCTAGTGCTACTTGAAAACGAAAGGACCTTGGATTTTCACGACAGTAATGTTAAAAAT CTCTACGAGAAAGTAAAGTCTCAGTTGAAGAACAATGCTAAGGAGATCGGCAATGGATGC TTTGAGTTCTATCACAAGTGCGATAACGAATGCATGGAAAGTGTGCGCAACGGAACCTAT GACTACCCCAAGTATTCCGAAGAGAGCAAGCTTAACAGAGAGAAGGTCGACGGAGTGAAG CTGGAAAGTATGGGGATCTACCAAATACTGGCAATATACAGCACAGTTGCAAGCAGTCTC GTGTTACTCGTCTCCCTTGGAGCAATCTCTTTCTGGATGTGTTCTAACGGCAGCCTGCAG TGCAGAATTTGTATC 450 ATGAAGGCAAACTTGCTCGTGCTGTTGTGCGCATTAGCCGCCGCCGATGCCGACACAATC TGCATCGGCTATCACGCTAACAACTCCACTGACACTGTGGATACCGTACTTGAAAAAAAT GTGACCGTCACACACTCGGTTAATCTCTTAGAGGACTCGCACAATGGCAAACTGTGTCGT CTGAAAGGGATCGCTCCACTTCAACTCGGGAAGTGTAATATTGCCGGGTGGCTGCTGGGC AACCCCGAGTGCGACCCTCTTCTGCCTGTACGGTCGTGGTCTTATATAGTGGAAACACCC AATAGTGAGAACGGCATATGCTATCCCGGAGACTTCATTGATTATGAAGAACTTAGGGAA CAGCTAAGCTCCGTGTCAAGCTTTGAAAGGTTTGAAATATTCCCCAAGGAGAGCTCCTGG CCTAATCACAATACCAACGGTGTGACCGCCGCCTGTTCGCACGAGGGCAAGAGCTCATTT TACAGGAATCTACTGTGGCTCACCGAGAAGGAAGGTTCGTACCCTAAGCTCAAGAATAGC TACGTGAATAAAAAGGGCAAAGAGGTACTGGTGCTGTGGGGGATTCACCACCCCCCTAAT TCGAAGGAGCAGCAAAACTTGTACCAGAATGAGAATGCCTACGTCTCTGTTGTCACTAGT AATTACAACCGTAGATTCACGCCTGAAATTGCTGAGCGACCAAAAGTTCGAGATCAGGCT GGCAGGATGAATTATTATTGGACCCTCCTGAAGCCCGGAGATACCATTATCTTCGAGGCT AATGGTAACCTGATCGCTCCTATGTACGCCTTCGCTTTGAGTCGAGGCTTCGGCAGCGGG ATAATTACGTCTAACGCTTCTATGCACGAGTGCAATACAAAGTGTCAGACTCCCCTTGGG GCAATCAATTCAAGCCTTCCCTATCAGAATATCCACCCTGTTACTATAGGGGAGTGTCCG AAATACGTTAGGTCGGCAAAGCTGAGGATGGTCACTGGCCTGCGAAATAACCCGTCCATT CAGTCCAGGGGGCTTTTCGGTGCTATCGCTGGATTTATTGAAGGTGGTTGGACTGGCATG ATCGACGGATGGTACGGGTATCACCACCAGAACGAACAGGGATCTGGGTACGCTGCCGAT CAAAAATCGACCCAGAACGCCATAAACGGCATTACAAATAAGGTGAATACCGTCATCGAA AAAATGAATATTCAATTCACCGCCGTAGGCAAAGAGTTTAATAAACTTGAGAAAAGGATG GAGAACCTCAATAAAAAAGTCGACGATGGGTTTCTGGATATCTGGACCTATAACGCTGAG CTTCTTGTGCTGCTCGAAAATGAACGCACACTGGATTTCCACGATTCCAACGTGAAAAAT TTGTACGAAAAGGTGAAGTCACAACTGAAGAATAACGCAAAGGAAATCGGGAATGGCTGT TTTGAATTCTATCACAAGTGTGACAACGAATGCATGGAGAGTGTCCGAAACGGAACCTAC GATTATCCAAAGTACTCGGAAGAATCTAAGCTGAATCGGGAGAAGGTGGACGGGGTCAAG CTGGAGTCAATGGGTATTTATCAGATCCTAGCGATTTACTCAACCGTGGCATCGAGCCTG GTCCTACTTGTTAGTCTTGGGGCAATAAGCTTCTGGATGTGCAGCAACGGCAGCTTGCAG TGCAGAATATGTATA 451 ATGAAGGCTAACCTGCTCGTTCTCTTATGTGCACTGGCCGCCGCAGACGCGGATACTATT TGTATAGGCTACCACGCGAATAACTCTACTGATACGGTGGACACAGTTCTCGAGAAAAAC GTGACAGTGACTCACTCCGTGAATCTGCTGGAGGATTCACACAACGGCAAACTGTGTCGA CTGAAAGGAATCGCACCGTTGCAACTTGGTAAGTGCAATATTGCCGGATGGCTCCTGGGA AACCCCGAATGCGATCCTTTGCTTCCCGTGCGGAGTTGGTCCTACATCGTGGAGACCCCT AACTCTGAGAACGGAATCTGTTATCCCGGGGATTTCATTGATTATGAAGAGCTCAGAGAA CAATTGAGTTCTGTTTCTAGCTTTGAGAGATTCGAGATTTTCCCTAAGGAGTCGTCCTGG CCAAATCACAACACTAACGGAGTAACCGCCGCCTGTTCTCACGAGGGCAAGTCAAGCTTT TACAGGAATCTCCTGTGGTTAACAGAAAAGGAAGGGAGTTACCCAAAACTAAAAAACTCG TACGTGAACAAGAAAGGCAAGGAGGTCCTGGTGCTGTGGGGAATTCATCACCCCCCGAAT TCCAAGGAACAACAGAATCTGTATCAAAACGAAAACGCTTATGTGTCCGTCGTGACATCG AACTACAATAGAAGATTTACCCCCGAGATTGCAGAGCGCCCTAAAGTCAGGGATCAGGCT GGGAGAATGAACTATTATTGGACACTGCTAAAGCCCGGCGATACAATTATCTTTGAGGCC AATGGCAATCTGATTGCTCCCATGTATGCATTTGCCCTGAGCAGAGGGTTTGGCAGTGGA ATCATTACCAGCAATGCTAGCATGCATGAATGTAATACAAAGTGTCAGACACCATTAGGA GCCATAAACAGTTCACTCCCTTATCAGAACATCCATCCCGTGACAATCGGAGAGTGTCCT AAATACGTCAGAAGTGCAAAATTGAGAATGGTTACCGGCTTGAGGAATAATCCATCTATT CAATCCCGCGGGCTCTTTGGAGCCATCGCTGGCTTTATTGAAGGAGGATGGACCGGAATG ATTGATGGATGGTATGGTTACCACCATCAGAATGAGCAGGGCTCCGGCTACGCCGCCGAC CAGAAGTCTACCCAAAACGCCATAAACGGAATCACCAATAAGGTGAACACTGTCATTGAA AAGATGAATATACAATTCACTGCCGTCGGGAAGGAGTTTAACAAACTCGAAAAGCGGATG GAGAATTTGAATAAAAAGGTCGACGACGGCTTCCTGGATATCTGGACATACAATGCCGAG CTCCTGGTCCTGTTGGAGAATGAACGCACACTCGATTTTCACGACAGCAATGTGAAGAAT CTTTACGAAAAGGTTAAAAGTCAGTTGAAAAACAACGCTAAAGAAATAGGTAATGGGTGT TTCGAGTTTTACCACAAGTGCGACAATGAGTGCATGGAATCTGTCAGAAATGGGACCTAC GACTACCCTAAGTACTCCGAAGAGTCTAAGCTGAATAGGGAGAAGGTGGATGGGGTGAAG CTGGAATCCATGGGCATCTACCAGATCCTCGCTATCTACAGCACAGTGGCCTCTAGCTTG GTGCTTTTGGTGTCACTTGGGGCGATTTCGTTCTGGATGTGCTCCAACGGAAGCCTGCAA TGCCGAATCTGTATC 452 ATGAAGGCTAACCTTCTTGTGCTTCTCTGTGCACTTGCTGCCGCAGATGCTGATACAATA TGCATCGGTTACCACGCTAATAATTCTACCGATACGGTTGACACGGTTCTTGAAAAGAAC GTCACAGTGACTCACAGCGTCAACCTCCTGGAGGACTCTCATAACGGAAAATTGTGCCGC CTCAAAGGCATTGCCCCATTGCAATTAGGCAAGTGTAATATTGCAGGTTGGCTCCTGGGT AACCCGGAATGCGACCCTCTGTTGCCTGTCAGGTCTTGGAGTTATATAGTCGAAACCCCA AATTCCGAAAATGGAATATGTTACCCTGGCGACTTTATCGACTACGAAGAACTGAGGGAG CAGCTTAGTTCCGTCAGTTCTTTCGAACGTTTCGAAATCTTCCCCAAGGAATCTAGTTGG CCCAACCATAACACCAACGGTGTGACGGCGGCATGCAGTCACGAGGGCAAGTCCAGCTTC TATAGAAACTTGCTGTGGTTAACCGAGAAAGAGGGAAGTTACCCTAAGCTGAAGAACAGC TACGTAAACAAAAAAGGCAAAGAAGTCCTGGTTCTCTGGGGCATTCACCACCCACCCAAT TCCAAGGAACAGCAAAATCTCTATCAAAATGAAAATGCTTATGTCTCTGTTGTGACCTCG AACTATAATCGGCGTTTTACCCCTGAGATCGCCGAGAGGCCTAAGGTCAGGGACCAAGCT GGCCGAATGAATTATTACTGGACCCTACTGAAGCCTGGCGATACCATAATCTTCGAGGCT AATGGAAATCTGATTGCGCCAATGTATGCTTTTGCACTGAGCCGCGGGTTTGGGAGCGGA ATTATCACCTCTAACGCATCTATGCACGAGTGTAACACAAAGTGTCAGACCCCGCTGGGG GCTATTAACTCCAGTTTGCCATACCAAAATATTCATCCGGTCACAATCGGTGAATGCCCC AAGTATGTTAGAAGCGCTAAGTTAAGAATGGTGACCGGGCTGCGTAACAACCCTAGTATC CAGTCACGCGGCCTCTTTGGGGCTATTGCCGGGTTCATCGAGGGAGGTTGGACTGGGATG ATCGACGGATGGTATGGGTACCACCATCAAAACGAGCAGGGATCAGGCTACGCCGCAGAC CAGAAGAGCACTCAGAACGCCATCAACGGGATCACTAATAAAGTTAATACCGTGATTGAA AAAATGAACATACAATTTACTGCAGTGGGCAAGGAGTTCAACAAACTAGAGAAACGCATG GAGAACTTGAACAAAAAAGTTGACGACGGATTTCTGGACATCTGGACATATAATGCAGAG CTGCTGGTCCTGCTAGAGAACGAACGGACCCTAGACTTCCATGACTCAAACGTCAAGAAT CTGTACGAGAAGGTGAAATCTCAGCTCAAAAATAATGCCAAAGAGATCGGCAATGGATGC TTTGAATTCTATCACAAGTGTGACAATGAGTGCATGGAGAGCGTGCGAAATGGAACTTAC GACTACCCAAAGTACAGCGAGGAGAGTAAGCTTAACAGGGAGAAGGTGGACGGCGTGAAG CTCGAAAGCATGGGGATATACCAGATCCTCGCCATATACTCTACTGTGGCGTCGTCTCTC GTGCTTTTGGTATCACTCGGCGCTATCAGCTTCTGGATGTGTTCCAATGGCAGCTTGCAG TGCCGGATATGCATT 453 ATGAAAGCCAATCTCTTAGTGCTACTGTGCGCCCTTGCCGCCGCAGACGCAGATACGATT TGCATTGGGTATCACGCAAACAATTCCACCGACACAGTGGATACCGTGCTCGAAAAGAAC GTAACTGTGACTCACTCTGTGAATTTACTCGAGGACAGTCACAACGGGAAGCTCTGCAGA CTTAAGGGGATCGCACCCTTGCAACTCGGAAAGTGTAACATTGCCGGGTGGCTTCTCGGC AACCCCGAGTGTGACCCTCTTCTTCCAGTTCGGAGCTGGAGTTATATAGTGGAAACGCCA AATTCCGAGAACGGCATATGTTACCCAGGAGACTTTATCGATTATGAAGAACTCCGCGAA CAGCTCAGCAGCGTGAGTTCTTTCGAACGTTTCGAGATCTTCCCAAAAGAGTCCAGTTGG CCAAATCATAACACCAATGGCGTAACAGCAGCGTGCAGCCACGAGGGAAAATCTAGCTTT TACAGGAACCTACTTTGGCTCACAGAAAAGGAGGGATCCTATCCTAAACTGAAGAATTCA TACGTCAATAAAAAAGGTAAAGAGGTGTTGGTGCTGTGGGGGATTCATCACCCACCAAAC TCCAAAGAACAGCAGAACCTGTACCAAAACGAGAACGCCTACGTCTCCGTGGTGACGAGC AACTATAACCGACGCTTTACCCCCGAAATCGCGGAGCGTCCAAAGGTGCGGGACCAGGCA GGGCGTATGAACTATTATTGGACACTTCTAAAACCCGGTGACACCATTATCTTTGAAGCG AACGGCAACTTGATTGCGCCAATGTATGCTTTCGCTCTGAGTCGGGGATTTGGATCGGGG ATTATTACCTCCAACGCGTCTATGCATGAATGTAACACCAAATGTCAAACCCCTCTTGGG GCCATCAACAGCTCCCTGCCATATCAGAACATTCACCCAGTCACCATCGGAGAATGCCCC AAGTATGTCCGCAGTGCTAAGCTCCGCATGGTAACCGGCCTGAGAAACAATCCCAGTATT CAGTCTAGGGGCCTCTTCGGCGCTATTGCAGGATTCATTGAGGGCGGATGGACAGGCATG ATCGATGGCTGGTACGGTTATCATCACCAGAACGAGCAAGGATCCGGCTACGCTGCGGAC CAGAAGAGCACCCAGAACGCTATTAACGGCATTACGAATAAGGTGAACACTGTCATCGAG AAGATGAACATTCAGTTTACCGCGGTTGGGAAGGAGTTCAACAAACTTGAAAAACGAATG GAGAATCTAAACAAAAAAGTCGACGATGGATTCCTGGATATCTGGACCTACAACGCTGAG CTGCTGGTGCTGCTGGAAAATGAGCGGACATTGGACTTCCACGATTCCAACGTGAAGAAT CTTTACGAGAAAGTTAAATCACAGTTGAAGAATAATGCCAAAGAGATTGGGAACGGCTGT TTTGAATTCTACCACAAATGCGATAACGAATGTATGGAATCTGTACGGAATGGTACGTAT GACTATCCAAAATACTCCGAAGAGTCCAAGCTGAACCGAGAAAAAGTGGACGGGGTCAAA CTGGAAAGCATGGGGATATACCAGATCCTGGCCATATATAGCACTGTGGCTTCTTCTTTG GTTCTCCTTGTGTCACTCGGGGCCATAAGCTTCTGGATGTGTTCAAACGGAAGCTTGCAG TGCAGAATTTGCATC 454 ATGAAGGCCAACTTACTGGTGTTGCTATGCGCTCTGGCCGCCGCTGACGCCGATACCATC TGTATTGGATACCACGCCAACAACAGCACCGACACTGTGGACACAGTGCTTGAGAAGAAT GTCACCGTCACACATAGTGTAAACTTGCTCGAAGATAGTCACAACGGGAAGCTGTGCCGC CTTAAAGGTATTGCACCACTGCAGTTAGGCAAGTGCAATATTGCCGGGTGGCTGCTTGGG AACCCCGAGTGTGATCCTCTATTGCCAGTTCGGTCGTGGAGCTATATCGTGGAGACACCG AACAGCGAAAACGGCATCTGTTATCCTGGAGATTTTATCGACTATGAGGAACTCAGGGAA CAGCTCTCGTCTGTGTCTAGCTTCGAACGCTTTGAAATTTTCCCAAAAGAGAGTTCCTGG CCAAATCATAACACTAACGGTGTGACTGCCGCTTGCTCCCATGAAGGCAAATCAAGCTTT TATAGGAATCTGTTGTGGTTGACTGAAAAAGAAGGCTCCTACCCGAAACTCAAGAACAGC TATGTGAACAAGAAAGGTAAGGAAGTGCTGGTGCTGTGGGGCATCCATCATCCTCCTAAC TCAAAGGAGCAGCAAAATCTTTACCAGAATGAAAACGCATACGTGTCCGTTGTAACCTCT AATTATAACCGCCGGTTCACCCCAGAAATCGCCGAGCGTCCAAAGGTTAGAGATCAAGCA GGGCGCATGAATTATTACTGGACACTGCTCAAGCCCGGCGATACCATCATCTTTGAGGCT AACGGCAACCTCATTGCTCCGATGTATGCGTTCGCTCTGAGTCGCGGCTTTGGCTCAGGC ATTATTACTTCCAATGCCTCTATGCACGAGTGCAACACTAAATGCCAGACGCCCCTGGGT GCAATCAACTCTAGCCTCCCATATCAGAACATACATCCCGTGACCATCGGCGAATGCCCT AAATACGTCCGGTCCGCAAAGCTGCGAATGGTGACGGGCCTGAGAAATAACCCCTCAATA CAGTCGCGAGGGCTGTTCGGCGCCATTGCCGGGTTTATTGAGGGGGGATGGACTGGGATG ATAGATGGTTGGTATGGGTATCATCATCAGAACGAGCAAGGGTCTGGGTATGCCGCTGAC CAAAAAAGCACCCAGAACGCCATAAACGGGATTACCAATAAGGTTAACACAGTTATTGAG AAGATGAATATTCAGTTTACCGCTGTCGGGAAAGAATTCAATAAATTGGAAAAAAGGATG GAGAACCTGAACAAAAAGGTGGACGATGGGTTTCTCGATATCTGGACATATAACGCTGAG CTTCTCGTACTGCTGGAAAATGAAAGGACGCTCGATTTCCATGATTCCAATGTCAAGAAT CTCTACGAGAAGGTCAAGTCTCAGCTGAAGAACAATGCCAAAGAGATCGGGAATGGATGT TTTGAGTTCTATCACAAGTGCGATAACGAATGCATGGAGTCCGTCAGGAACGGCACCTAT GATTACCCTAAGTACAGTGAAGAAAGCAAACTTAATAGGGAAAAGGTGGATGGTGTGAAG CTGGAGTCAATGGGCATTTACCAGATTCTGGCCATTTACAGTACAGTAGCCTCTAGTCTG GTGCTGCTTGTCAGCCTTGGCGCCATCTCCTTTTGGATGTGTAGCAACGGATCACTGCAG TGCAGGATCTGCATT 455 ATGAAAGCAAACTTGCTTGTGCTGTTATGCGCTCTGGCAGCTGCGGACGCCGATACTATC TGCATCGGTTACCACGCTAACAATTCAACAGATACCGTTGATACTGTGCTGGAGAAGAAC GTGACCGTCACCCACAGTGTGAACCTCTTGGAAGACAGCCACAACGGAAAACTGTGCCGC CTGAAGGGCATCGCGCCGTTACAGCTGGGAAAGTGCAATATCGCCGGATGGCTTTTGGGT AATCCAGAATGTGATCCATTGCTCCCCGTGAGAAGCTGGAGCTATATTGTTGAAACCCCT AACTCAGAGAATGGGATCTGCTACCCCGGGGACTTCATTGACTACGAGGAACTGCGCGAG CAGTTGTCATCCGTCAGTTCATTCGAGCGGTTTGAAATATTTCCCAAGGAGTCAAGTTGG CCAAACCACAACACGAACGGAGTAACAGCGGCTTGTAGCCATGAAGGTAAAAGCTCTTTT TACAGGAATCTGCTGTGGTTGACTGAGAAGGAGGGCTCCTACCCCAAACTGAAAAACAGC TACGTGAACAAAAAGGGCAAGGAGGTCCTGGTGCTCTGGGGAATTCACCATCCGCCCAAT TCCAAAGAGCAGCAGAATTTATACCAAAATGAGAACGCCTACGTTTCTGTCGTCACGTCA AATTATAACCGACGCTTTACACCTGAAATAGCTGAGAGACCCAAGGTGAGAGATCAGGCT GGGAGGATGAATTACTATTGGACTCTGCTAAAACCTGGAGACACTATAATCTTCGAAGCC AACGGGAACCTGATTGCCCCTATGTACGCATTTGCTTTATCCCGAGGGTTTGGAAGCGGG ATCATTACTTCAAATGCTTCTATGCACGAGTGCAATACCAAATGCCAGACACCTTTAGGC GCTATCAATTCATCTCTGCCTTATCAGAACATTCACCCAGTGACAATAGGAGAGTGTCCT AAGTATGTCCGCTCCGCGAAGCTTCGTATGGTCACAGGCCTCAGGAATAACCCAAGTATC CAGTCGAGAGGCCTTTTTGGTGCCATCGCTGGCTTTATCGAAGGAGGGTGGACCGGCATG ATTGATGGGTGGTATGGATACCATCATCAGAACGAGCAAGGCTCAGGTTACGCCGCGGAC CAGAAGTCCACGCAAAATGCCATTAACGGCATCACGAACAAAGTCAACACCGTTATCGAG AAGATGAATATACAGTTCACAGCCGTAGGCAAAGAATTTAATAAACTCGAAAAGCGGATG GAGAATTTAAACAAAAAAGTCGATGATGGATTTCTCGATATCTGGACTTATAACGCCGAA CTTCTAGTGCTGCTTGAGAACGAGAGAACGCTTGATTTTCACGACAGTAACGTTAAAAAC CTGTACGAAAAGGTAAAGTCCCAACTGAAAAACAATGCCAAAGAAATTGGAAACGGTTGC TTTGAATTTTACCACAAGTGCGATAATGAGTGCATGGAAAGTGTAAGAAATGGCACGTAT GACTATCCCAAATACTCCGAAGAAAGCAAGCTCAATCGTGAGAAGGTGGATGGTGTGAAG CTGGAATCGATGGGGATTTATCAGATCCTAGCTATCTATTCAACAGTCGCCTCTAGTCTT GTTCTTCTTGTATCTCTTGGAGCCATCTCATTTTGGATGTGTTCAAACGGATCCCTGCAG TGTCGGATCTGTATC 456 ATGAAGGCTAACCTGCTGGTTCTACTCTGCGCACTCGCAGCTGCGGACGCCGACACAATT TGTATTGGATATCACGCTAACAATAGCACCGATACCGTAGACACCGTACTGGAAAAGAAT GTGACGGTCACACACTCAGTAAATCTCCTGGAAGACAGCCATAATGGCAAGCTGTGTAGA TTAAAAGGGATTGCTCCTCTCCAGTTGGGCAAATGTAACATCGCCGGTTGGCTGCTGGGG AACCCCGAGTGCGACCCATTGCTGCCCGTAAGGAGCTGGTCCTATATAGTTGAGACACCC AATTCTGAGAATGGCATCTGCTACCCCGGAGATTTTATCGATTATGAGGAGTTGCGTGAG CAGCTCTCTAGCGTGAGCTCGTTTGAAAGATTTGAAATTTTTCCGAAAGAATCTAGTTGG CCCAACCACAATACGAACGGAGTGACTGCCGCCTGCTCCCACGAGGGAAAATCCTCATTT TACAGGAACTTACTCTGGCTTACTGAGAAGGAAGGTAGCTACCCAAAGCTCAAGAACAGC TACGTCAACAAGAAGGGCAAGGAAGTCCTGGTCCTGTGGGGAATCCATCATCCGCCAAAC TCCAAGGAGCAACAGAATCTATATCAGAATGAGAATGCCTACGTTTCAGTGGTTACGTCT AATTATAACCGCAGGTTTACCCCCGAGATCGCTGAGCGCCCCAAAGTTAGAGACCAGGCA GGGCGCATGAACTACTATTGGACCCTCCTGAAACCTGGCGACACAATTATCTTCGAGGCA AACGGTAATCTCATCGCGCCTATGTACGCTTTTGCCCTTAGCCGGGGTTTTGGATCAGGC ATCATAACTTCTAACGCCTCTATGCACGAATGTAACACCAAGTGTCAGACCCCCCTAGGA GCTATCAACAGCTCGCTTCCTTACCAGAACATTCATCCCGTGACCATAGGTGAGTGTCCA AAATACGTCAGGAGTGCAAAACTAAGGATGGTTACCGGACTCCGGAATAACCCTTCGATT CAGTCGCGCGGGCTCTTTGGAGCAATCGCCGGGTTCATCGAAGGCGGGTGGACCGGGATG ATTGACGGTTGGTACGGCTACCATCACCAAAACGAACAAGGCTCAGGTTATGCAGCTGAC CAGAAGTCCACTCAGAATGCCATAAATGGCATTACCAACAAAGTTAATACAGTCATTGAG AAGATGAATATACAGTTCACCGCGGTGGGCAAAGAGTTCAACAAACTGGAGAAACGTATG GAAAACTTGAACAAAAAAGTGGACGATGGGTTCTTGGACATCTGGACGTATAATGCCGAG TTATTAGTGCTGCTGGAAAATGAAAGAACGTTAGACTTCCACGACTCTAATGTTAAAAAT TTGTACGAAAAGGTCAAATCCCAACTGAAAAATAACGCCAAGGAAATAGGCAATGGCTGT TTTGAATTCTATCATAAGTGCGATAACGAGTGTATGGAGAGTGTTCGCAATGGTACATAC GACTACCCTAAATACTCCGAGGAAAGTAAGCTGAACAGGGAAAAGGTCGATGGAGTCAAG CTGGAATCCATGGGGATTTATCAGATCCTGGCCATTTATAGCACTGTAGCCTCCTCCCTG GTGCTGCTGGTATCACTCGGCGCAATAAGCTTCTGGATGTGTTCTAACGGGAGCCTGCAA TGCAGAATATGCATT 457 ATGAAAGCAAACCTCCTCGTGTTGCTCTGTGCCCTGGCTGCAGCCGACGCCGACACCATA TGTATCGGGTACCACGCCAATAACTCCACTGATACCGTCGATACCGTCCTTGAGAAAAAT GTGACAGTCACACACAGCGTTAATTTATTGGAGGACAGCCACAACGGCAAGCTCTGTAGG CTGAAAGGGATCGCCCCCTTACAGCTGGGGAAATGTAATATCGCTGGATGGCTGCTGGGA AACCCCGAGTGCGACCCCTTGCTGCCTGTGAGGTCTTGGAGCTACATTGTTGAGACCCCT AACAGCGAGAACGGCATTTGTTACCCTGGCGACTTCATTGACTACGAGGAGCTGAGGGAA CAATTGTCATCTGTCAGCTCATTTGAGCGATTCGAGATCTTTCCCAAGGAATCGTCATGG CCAAATCACAACACAAACGGGGTGACCGCGGCTTGCTCACATGAAGGAAAGAGCTCCTTT TACCGAAATCTTCTGTGGCTGACGGAGAAGGAAGGATCATACCCAAAATTGAAAAACTCC TATGTGAACAAGAAAGGTAAAGAGGTCCTTGTTTTATGGGGCATTCACCACCCACCTAAC TCAAAAGAACAGCAAAACCTGTACCAGAACGAGAATGCATACGTTTCAGTAGTCACCTCT AACTATAATAGGAGATTCACCCCCGAAATCGCCGAGAGGCCAAAGGTACGGGATCAGGCT GGCAGGATGAATTACTATTGGACCCTACTTAAACCTGGAGACACGATCATCTTCGAGGCA AATGGAAACCTCATCGCCCCTATGTATGCCTTTGCCCTTAGCCGAGGGTTTGGATCAGGG ATAATAACCTCTAACGCCAGTATGCACGAATGCAATACGAAGTGTCAAACCCCTCTGGGA GCAATAAATTCTTCCCTTCCTTATCAGAACATTCACCCCGTCACAATTGGAGAGTGCCCC AAATACGTCAGGTCCGCCAAACTGAGAATGGTTACCGGCTTGCGGAATAATCCGAGCATT CAGAGCCGCGGATTATTTGGTGCTATTGCTGGCTTTATCGAAGGAGGGTGGACCGGAATG ATCGACGGGTGGTACGGCTACCATCATCAGAACGAGCAGGGTAGCGGTTACGCTGCCGAT CAGAAATCCACTCAGAATGCCATCAATGGCATTACTAACAAAGTAAATACTGTGATTGAA AAGATGAACATCCAGTTTACCGCAGTAGGAAAAGAGTTCAACAAATTGGAGAAAAGGATG GAAAACCTCAACAAAAAAGTCGACGATGGATTCCTTGATATTTGGACATACAACGCTGAG CTGCTAGTGCTGCTGGAGAACGAGCGAACACTCGATTTCCATGATAGCAACGTCAAAAAC CTGTACGAGAAGGTCAAAAGCCAGCTGAAAAATAACGCTAAGGAGATTGGGAATGGCTGT TTCGAATTCTACCACAAATGTGATAATGAATGCATGGAGAGTGTGCGGAATGGGACATAC GACTACCCAAAATATTCTGAAGAGAGTAAACTTAATCGAGAGAAAGTGGATGGTGTTAAA CTTGAGTCTATGGGCATTTACCAGATCCTGGCAATTTACAGTACCGTCGCTTCTTCTTTG GTCCTACTAGTGAGCCTCGGAGCAATCAGCTTCTGGATGTGTAGTAACGGGAGCCTTCAG TGTCGAATTTGCATC 458 ATGAAAGCTAATCTGCTCGTACTGCTCTGCGCTCTGGCTGCCGCTGATGCCGACACCATC TGTATTGGATATCACGCAAACAATTCTACTGATACCGTGGACACCGTGCTCGAGAAAAAC GTGACCGTGACGCATTCCGTTAATCTGCTGGAAGATTCACACAACGGAAAGCTGTGTAGA CTGAAGGGAATCGCCCCACTGCAATTGGGTAAATGTAACATTGCAGGATGGCTTCTGGGT AATCCTGAATGCGATCCACTGCTCCCTGTTAGATCATGGTCATATATCGTCGAAACACCG AATTCTGAAAATGGTATTTGCTACCCTGGCGATTTCATCGACTACGAAGAGCTGAGAGAG CAGCTATCTAGCGTGAGTAGCTTCGAACGCTTCGAAATTTTTCCCAAAGAGAGCTCTTGG CCGAACCACAATACCAATGGCGTGACCGCCGCATGCAGCCATGAGGGCAAATCTTCTTTC TACAGAAATCTACTTTGGCTGACCGAAAAAGAGGGAAGTTACCCAAAGCTGAAAAATTCC TATGTCAACAAAAAAGGGAAGGAGGTACTTGTGTTATGGGGAATTCACCACCCCCCTAAC TCCAAGGAGCAGCAGAACCTGTATCAGAATGAGAACGCGTATGTTTCAGTGGTCACCAGC AACTATAATCGTCGGTTCACCCCTGAGATCGCCGAACGGCCCAAGGTGAGAGATCAGGCT GGAAGAATGAATTACTATTGGACCTTGCTGAAGCCTGGGGATACCATCATCTTTGAAGCT AATGGAAACCTGATCGCGCCTATGTACGCATTCGCCCTATCCCGTGGCTTCGGTTCCGGC ATTATCACCTCAAATGCCTCAATGCACGAGTGCAACACTAAATGTCAGACCCCGCTGGGT GCCATCAACTCCAGCCTTCCCTACCAAAACATACATCCAGTGACGATTGGCGAGTGCCCA AAGTACGTCCGCTCTGCCAAGCTACGCATGGTCACGGGCCTGCGAAATAACCCCTCTATA CAATCCCGTGGGCTGTTTGGCGCGATTGCCGGGTTCATCGAGGGAGGATGGACAGGTATG ATCGATGGCTGGTACGGATACCATCATCAGAACGAACAGGGCTCCGGCTACGCTGCGGAC CAGAAGTCTACGCAAAACGCAATTAATGGAATCACAAACAAGGTGAACACTGTGATCGAG AAAATGAATATTCAGTTTACCGCCGTCGGTAAAGAATTCAATAAGCTCGAGAAGAGAATG GAGAACTTGAACAAAAAAGTGGATGATGGGTTTCTCGATATTTGGACATATAACGCGGAA CTCCTGGTGCTGCTCGAGAATGAGCGCACCCTGGATTTTCACGACTCTAACGTCAAGAAT TTATACGAGAAAGTAAAATCCCAGCTGAAGAACAATGCTAAAGAAATTGGCAACGGATGT TTCGAGTTTTATCATAAATGCGATAATGAGTGCATGGAGAGCGTGCGCAATGGAACATAC GACTACCCTAAATACAGCGAGGAATCTAAGCTGAATAGAGAGAAGGTAGACGGAGTCAAG CTGGAATCTATGGGAATATATCAAATTTTAGCTATTTACTCCACAGTTGCTTCATCCCTG GTCTTACTGGTTTCCCTCGGCGCGATCTCGTTTTGGATGTGCAGTAATGGCTCCCTTCAG TGTCGAATCTGCATC 459 ATGAAAGCTAATCTGTTGGTGCTGCTCTGCGCTTTGGCCGCTGCCGATGCAGATACCATC TGTATCGGCTATCACGCGAACAATTCCACAGATACAGTGGACACCGTCCTGGAGAAAAAT GTGACCGTGACCCACTCTGTCAACCTGCTCGAAGACAGCCATAACGGCAAACTGTGTAGA CTGAAGGGCATTGCACCTTTACAGCTGGGCAAGTGCAATATAGCTGGATGGCTCCTCGGC AATCCCGAATGCGACCCTCTACTGCCCGTGAGAAGCTGGTCATATATCGTTGAAACCCCG AATTCCGAGAATGGAATCTGCTATCCCGGAGATTTCATCGACTATGAAGAGCTCAGGGAA CAGCTGTCCTCTGTATCCTCCTTTGAACGTTTTGAGATTTTCCCAAAGGAGTCATCTTGG CCTAACCACAACACGAACGGGGTAACCGCAGCCTGCAGTCACGAAGGTAAGAGCAGCTTT TACAGGAATCTGCTGTGGCTAACCGAGAAAGAGGGCAGTTATCCTAAACTGAAAAATTCA TATGTGAACAAGAAAGGAAAGGAAGTGCTGGTGCTTTGGGGAATCCACCATCCGCCCAAC AGCAAGGAGCAGCAGAACCTATACCAGAACGAAAACGCTTATGTGTCAGTGGTGACTAGC AACTACAACCGACGTTTTACCCCCGAGATTGCCGAGCGACCCAAGGTGAGAGACCAGGCC GGTCGCATGAACTACTACTGGACACTCCTTAAGCCAGGCGATACAATCATATTTGAAGCT AACGGGAACCTCATTGCTCCTATGTACGCTTTCGCGCTGTCTAGGGGTTTCGGCTCCGGA ATAATTACAAGCAATGCTTCCATGCACGAGTGCAATACCAAGTGTCAGACTCCCCTGGGG GCCATTAACAGCAGTCTGCCATACCAAAATATTCATCCAGTAACAATCGGCGAGTGTCCA AAGTACGTGCGATCTGCCAAGTTACGAATGGTGACCGGCCTGCGCAATAACCCCTCAATT CAGTCTAGGGGCTTATTCGGGGCTATCGCCGGCTTCATTGAGGGAGGATGGACAGGAATG ATCGATGGATGGTACGGCTACCATCACCAGAATGAGCAAGGCAGCGGTTACGCTGCCGAC CAGAAATCGACACAGAATGCTATCAATGGAATCACTAACAAAGTCAACACGGTGATTGAA AAGATGAATATCCAATTCACTGCAGTGGGCAAGGAATTCAACAAATTAGAGAAGCGGATG GAGAACCTGAATAAAAAAGTTGATGACGGTTTCCTGGATATCTGGACATACAATGCAGAA CTTCTCGTCCTGCTCGAGAACGAGCGAACTCTCGATTTTCACGATTCTAATGTCAAAAAT CTGTATGAAAAGGTGAAGTCCCAGCTGAAGAACAACGCAAAGGAAATCGGGAATGGATGC TTCGAGTTTTACCATAAATGTGATAACGAGTGCATGGAAAGCGTCCGAAATGGCACTTAT GACTATCCAAAATACTCAGAGGAGAGTAAACTTAACCGCGAGAAGGTTGATGGCGTTAAA CTGGAATCCATGGGCATTTACCAGATCTTGGCTATCTATAGCACGGTGGCTTCTTCGCTG GTGCTCTTGGTCAGTCTCGGTGCCATCTCATTCTGGATGTGTTCGAACGGATCTCTTCAA TGCCGAATCTGTATA 460 ATGAAAGCCAACCTTCTAGTTTTACTATGTGCTCTCGCTGCTGCTGACGCCGACACTATT TGTATTGGATATCACGCAAATAATTCCACAGATACTGTCGACACCGTTTTGGAAAAGAAC GTGACTGTCACTCACTCAGTCAACCTGCTCGAAGATTCTCACAATGGCAAATTATGCCGC CTCAAGGGAATCGCTCCGCTCCAATTGGGAAAATGTAACATCGCAGGATGGCTCCTCGGC AATCCTGAATGCGACCCTCTCCTGCCCGTCCGCTCTTGGTCATACATAGTGGAAACTCCC AACAGTGAAAATGGAATATGTTACCCCGGTGACTTCATCGACTATGAGGAATTGCGCGAG CAACTGTCCTCAGTTTCCTCGTTCGAAAGATTTGAGATCTTCCCCAAGGAGTCCTCCTGG CCCAATCACAATACGAATGGCGTTACGGCAGCCTGCTCTCATGAGGGGAAATCCTCATTC TACCGCAACCTGCTCTGGCTGACAGAGAAGGAGGGGTCCTACCCTAAGCTCAAAAATTCC TATGTGAATAAAAAGGGCAAAGAAGTACTGGTCCTGTGGGGCATTCACCATCCCCCAAAT AGTAAAGAACAACAGAACCTCTACCAGAATGAGAACGCTTACGTGAGTGTGGTCACTAGC AACTACAACAGGAGATTCACACCCGAGATAGCGGAACGACCCAAGGTCCGCGATCAGGCT GGTCGCATGAATTACTACTGGACCTTGCTGAAGCCCGGAGATACGATTATTTTTGAGGCC AATGGCAATCTTATCGCCCCAATGTACGCCTTTGCACTGCAGCGTGGGTTCGGAAGTGGA ATCATAACTTCAAATGCCTCCATGCATGAGTGCAATACAAAATGTCAGACCCCTCTCGGA GCCATCAACTCATCACTGCCATACCAGAATATTCACCCTGTTACAATTGGAGAGTGTCCA AAATACGTCAGAAGTGCAAAACTGCGCATGGTTACCGGACTACGTAACAACCCGTCCATC CAGTCAAGAGGGCTGTTTGGAGCCATCGCAGGATTTATAGAGGGAGGCTGGACCGGGATG ATTGATGGCTGGTACGGCTACCATCACCAAAATGAGCAGGGAAGTGGGTATGCTGCCGAC CAGAAATCCACCCAAAACGCGATCAATGGTATCACCAACAAAGTCAATACCGTGATCGAA AAAATGAACATACAGTTTACAGCAGTGGGAAAGGAATTCAATAAACTTGAGAAACGCATG GAGAATCTGAATAAAAAGGTCGACGATGGCTTCCTAGATATTTGGACCTACAATGCAGAA TTACTGGTATTGTTGGAGAATGAGCGGACCCTCGACTTCCATGATTCGAACGTTAAAAAC CTCTACGAGAAGGTAAAGTCGCAACTGAAAAACAACGCTAAGGAGATCGGGAACGGCTGC TTCGAATTTTATCACAAATGCGACAACGAATGCATGGAATCAGTGCGAAATGGCACCTAT GATTATCCAAAGTATTCGGAGGAGTCAAAGCTGAATAGAGAGAAGGTGGATGGTGTGAAG TTGGAGAGTATGGGGATTTACCAGATCTTAGCAATCTATTCCACGGTTGCTAGTTCCCTC GTGTTACTTGTGAGCCTGGGTGCGATCAGTTTCTGGATGTGCAGTAACGGTTCACTGCAA TGCAGAATCTGCATC 461 ATGAAAGCTAATCTCCTGGTTTTGTTGTGTGCACTGGCCGCTGCCGACGCCGACACAATC TGCATAGGATACCATGCTAACAACAGTACAGATACAGTTGACACCGTGCTGGAAAAGAAT GTTACTGTAACCCATAGCGTTAACTTGCTAGAGGACTCTCATAATGGAAAGCTCTGTAGG CTTAAAGGGATCGCCCCCTTACAATTGGGCAAGTGCAATATCGCCGGATGGCTGCTCGGG AACCCTGAGTGTGATCCATTGCTGCCAGTTCGTTCCTGGTCTTACATAGTTGAAACGCCA AACTCCGAGAACGGGATCTGTTACCCAGGTGACTTCATTGATTACGAAGAACTGAGAGAA CAGCTAAGTTCTGTGTCTAGCTTCGAGAGATTCGAGATCTTTCCCAAAGAGTCAAGTTGG CCTAACCACAATACCAACGGGGTTACCGCGGCTTGCTCCCACGAAGGTAAAAGCTCATTC TACCGGAACCTTTTGTGGCTCACTGAGAAAGAGGGTAGCTACCCAAAGCTCAAGAACTCC TACGTGAATAAGAAGGGGAAGGAGGTGCTCGTTTTATGGGGTATCCACCACCCCCCTAAT AGTAAGGAACAGCAAAATCTCTATCAGAACGAAAACGCATATGTCTCGGTGGTGACCTCA AACTATAATCGGAGATTCACTCCAGAGATCGCCGAGAGACCCAAAGTCCGGGACCAGGCA GGAAGGATGAACTATTATTGGACTTTACTGAAGCCCGGGGATACTATTATTTTTGAAGCC AATGGCAATCTTATTGCCCCCATGTACGCTTTCGCCCTGAGTCGCGGCTTCGGGAGTGGC ATTATTACTTCCAATGCCTCGATGCATGAGTGCAATACGAAGTGTCAGACCCCATTAGGA GCTATCAATAGCAGCCTGCCATATCAGAACATCCACCCGGTGACTATTGGAGAGTGTCCA AAGTACGTTAGGTCCGCCAAGTTACGGATGGTAACAGGCCTCCGCAATAATCCTTCTATC CAAAGTCGGGGGCTGTTTGGAGCAATCGCCGGCTTCATCGAGGGAGGTTGGACTGGGATG ATTGACGGATGGTATGGGTACCATCATCAGAATGAGCAAGGCAGTGGCTACGCAGCCGAC CAGAAGTCAACCCAAAACGCCATCAATGGAATCACGAATAAAGTGAACACAGTGATCGAG AAGATGAACATTCAGTTCACTGCAGTGGGGAAGGAATTTAACAAGTTGGAGAAGAGAATG GAGAACCTGAACAAGAAGGTAGACGATGGATTCCTAGACATATGGACATATAATGCCGAG CTGTTGGTCCTCCTCGAAAACGAAAGAACACTGGACTTTCATGACAGTAACGTGAAGAAT TTGTATGAGAAAGTTAAGTCTCAACTGAAAAACAACGCCAAAGAAATAGGGAACGGTTGT TTCGAGTTCTATCATAAGTGCGATAACGAGTGCATGGAGTCTGTGCGGAATGGCACGTAC GATTATCCAAAATACTCCGAGGAGTCCAAACTTAACAGAGAGAAAGTGGATGGCGTGAAA CTTGAAAGCATGGGCATTTACCAAATCCTCGCCATTTACAGCACAGTCGCTTCTAGTCTA GTACTGCTTGTATCACTCGGCGCCATATCATTCTGGATGTGTAGTAATGGCAGCCTGCAG TGCCGAATTTGCATT 462 ATGAAAGCCAACCTGCTCGTACTCCTGTGTGCCCTGGCTGCCGCTGACGCCGATACTATT TGCATAGGGTATCACGCCAATAATTCAACTGACACCGTCGATACCGTTCTTGAGAAGAAC GTGACCGTCACACATTCAGTTAACCTTCTTGAGGACTCTCATAATGGTAAATTGTGTCGC CTCAAGGGTATCGCACCGCTACAACTAGGCAAGTGTAATATAGCAGGGTGGTTGTTGGGA AACCCTGAGTGTGACCCGCTGCTGCCCGTTCGCAGTTGGTCTTACATCGTCGAGACACCA AACTCTGAGAACGGGATTTGCTATCCAGGGGATTTTATCGACTATGAAGAGCTTCGCGAG CAGTTGAGCAGTGTTTCCTCTTTTGAGCGTTTTGAAATTTTCCCGAAAGAGAGTAGCTGG CCTAACCATAACACAAACGGGGTCACCGCAGCTTGCTCTCATGAGGGGAAGTCAAGCTTC TATCGGAATCTGCTGTGGCTGACGGAAAAAGAAGGCTCGTACCCAAAGCTAAAAAATTCA TACGTGAACAAGAAGGGGAAAGAGGTCCTGGTCCTGTGGGGGATCCACCATCCACCTAAT AGTAAAGAGCAGCAAAATTTGTACCAAAACGAGAATGCGTACGTGAGCGTAGTGACATCA AACTACAACCGCCGCTTCACTCCTGAGATTGCTGAACGGCCCAAGGTGCGTGATCAGGCC GGCAGGATGAACTATTATTGGACTTTGCTAAAACCTGGGGATACTATAATTTTTGAGGCG AATGGCAATCTAATCGCACCGATGTATGCCTTCGCCTTGAGCCGGGGCTTCGGCAGTGGG ATTATTACCAGTAACGCCTCCATGCACGAATGTAACACAAAGTGTCAGACTCCATTAGGG GCAATCAACTCGTCACTTCCGTATCAAAATATTCACCCTGTGACCATCGGCGAGTGTCCA AAATACGTTAGAAGTGCCAAGCTGAGAATGGTGACGGGTCTCCGGAACAATCCCTCAATC CAATCAAGGGGGTTATTTGGCGCTATTGCTGGTTTCATTGAGGGGGGATGGACCGGAATG ATCGACGGCTGGTACGGATATCATCATCAGAACGAACAGGGGTCCGGCTATGCTGCCGAC CAGAAGTCCACTCAGAACGCGATCAATGGGATCACCAACAAGGTCAACACCGTCATCGAA AAGATGAATATTCAGTTTACAGCCGTCGGAAAGGAATTCAATAAGTTGGAGAAACGCATG GAAAACTTAAACAAGAAAGTGGACGACGGATTCTTAGACATATGGACTTATAACGCAGAG CTGCTTGTACTCCTGGAGAATGAGCGAACCTTGGATTTTCATGATTCAAACGTTAAGAAC TTATATGAGAAGGTGAAGTCTCAACTCAAAAACAATGCCAAAGAAATCGGGAATGGGTGC TTCGAATTCTATCATAAATGTGATAACGAGTGTATGGAGAGCGTGCGGAATGGAACTTAT GACTACCCCAAATACAGCGAAGAAAGCAAGTTGAACAGAGAGAAGGTGGATGGCGTGAAG CTGGAAAGCATGGGGATTTACCAGATTCTTGCAATCTATTCTACTGTTGCATCCAGTCTA GTTCTGCTCGTCTCTCTGGGGGCAATCAGCTTTTGGATGTGCTCTAATGGTTCCCTGCAG TGCCGTATCTGCATA 463 ATGAAAGCAAACCTTCTGGTACTGCTCTGCGCCTTAGCCGCCGCTGATGCGGACACGATT TGTATTGGCTATCACGCCAATAATTCAACAGATACTGTCGACACAGTCTTGGAGAAAAAT GTGACTGTAACCCATTCTGTCAATCTGCTCGAGGATTCACACAATGGAAAACTGTGTCGG CTTAAAGGAATCGCTCCTCTGCAGTTGGGCAAGTGTAATATAGCTGGCTGGCTGTTAGGA AACCCAGAATGCGATCCTCTCTTACCTGTGCGATCCTGGTCTTACATCGTTGAGACACCG AACAGCGAGAATGGTATATGCTACCCGGGTGACTTTATCGATTATGAAGAATTGAGAGAA CAGCTGTCAAGCGTCAGCTCTTTCGAACGATTCGAGATCTTTCCCAAAGAGTCAAGCTGG CCTAACCACAATACAAATGGAGTGACAGCTGCGTGTTCCCATGAAGGCAAGAGTTCTTTC TACCGAAACCTGCTTTGGCTGACCGAGAAGGAGGGATCATACCCTAAGTTAAAAAATTCA TACGTCAACAAGAAGGGAAAAGAGGTACTAGTTCTTTGGGGTATTCACCACCCACCCAAC TCCAAAGAGCAGCAGAATCTGTATCAAAATGAAAACGCGTACGTCTCCGTGGTGACCTCG AACTACAATCGACGATTCACTCCCGAAATCGCTGAGAGGCCCAAAGTCCGGGATCAGGCC GGACGCATGAATTATTACTGGACTCTACTAAAGCCAGGTGATACAATTATCTTCGAAGCC AATGGCAATCTTATCGCTCCCATGTACGCATTCGCTCTGAGCCGTGGTTTTGGGTCTGGA ATCATCACCTCCAACGCTTCTATGCATGAATGTAATACAAAATGCCAGACTCCGTTAGGG GCAATCAACAGTTCACTGCCATACCAAAACATCCACCCCGTGACTATTGGGGAGTGCCCA AAGTATGTCCGGAGCGCCAAACTCCGGATGGTCACCGGCCTACGCAATAACCCCAGTATC CAGTCTAGGGGATTGTTCGGTGCTATCGCAGGTTTTATTGAGGGCGGCTGGACAGGAATG ATCGACGGATGGTATGGGTATCATCACCAGAATGAACAAGGCTCCGGGTATGCGGCTGAC CAAAAATCCACGCAGAACGCAATCAACGGAATCACCAATAAAGTGAATACTGTGATAGAA AAGATGAACATTCAGTTCACGGCTGTAGGCAAGGAGTTCAATAAGCTGGAGAAGAGAATG GAGAACCTAAATAAGAAGGTCGATGACGGCTTCCTTGACATCTGGACTTACAATGCAGAA CTGCTGGTACTGCTTGAGAACGAACGCACCCTGGATTTCCACGACTCTAATGTGAAGAAC CTATACGAAAAAGTGAAGTCCCAGCTGAAAAACAATGCTAAAGAGATAGGCAACGGCTGC TTCGAATTCTATCATAAATGCGACAACGAGTGCATGGAGTCAGTCCGAAATGGTACGTAC GATTACCCAAAATATTCTGAAGAGTCCAAGCTAAATAGAGAAAAGGTGGACGGCGTAAAA CTCGAGTCCATGGGCATCTACCAGATTCTGGCCATCTACAGTACGGTGGCTTCATCGCTT GTACTCCTGGTGAGCCTAGGGGCCATCTCTTTTTGGATGTGTTCTAACGGTTCCCTGCAG TGCCGCATTTGTATT 464 ATGAAAGCTAACCTGCTGGTACTCTTATGCGCTCTGGCCGCTGCAGACGCCGATACCATC TGTATCGGGTATCATGCCAACAATAGCACCGACACCGTGGATACAGTCCTAGAAAAGAAT GTGACCGTCACTCACTCAGTGAACCTATTAGAAGATTCCCACAACGGCAAGTTGTGTCGC CTCAAAGGCATCGCCCCACTGCAACTTGGGAAATGCAACATAGCCGGGTGGCTGCTGGGC AACCCAGAGTGCGATCCCCTGTTGCCAGTGCGCAGTTGGTCATATATCGTGGAGACTCCA AATTCAGAAAATGGGATTTGCTATCCAGGGGACTTCATCGACTACGAAGAACTGCGCGAA CAGCTGTCCAGCGTGAGTTCCTTCGAACGATTTGAAATTTTCCCAAAGGAGAGCAGCTGG CCTAACCACAACACGAACGGAGTGACTGCCGCTTGCAGCCACGAGGGAAAGAGCTCTTTC TACCGCAACCTTCTGTGGTTGACAGAGAAGGAAGGGAGCTACCCCAAACTGAAGAACTCC TACGTTAATAAGAAAGGTAAGGAAGTGCTAGTGCTCTGGGGTATCCATCATCCACCAAAT AGCAAAGAGCAACAGAATCTGTATCAGAACGAGAACGCTTACGTGTCAGTTGTCACTTCC AACTATAACCGCCGGTTCACTCCAGAGATCGCTGAGCGCCCCAAGGTGCGCGATCAGGCT GGCCGCATGAACTATTACTGGACCTTGCTGAAGCCAGGGGACACAATTATCTTTGAGGCC AATGGAAATCTCATCGCACCGATGTACGCCTTTGCCCTTTCCCGGGGCTTCGGGTCTGGC ATCATTACCTCGAATGCTTCGATGCACGAGTGCAACACCAAGTGCCAAACTCCCTTGGGA GCTATTAATTCTTCACTCCCATACCAGAATATTCACCCAGTTACAATCGGCGAGTGTCCA AAGTACGTGCGTTCCGCAAAACTGCGGATGGTTACAGGTCTGCGAAACAATCCAAGTATA CAGAGTAGAGGACTTTTTGGAGCTATTGCCGGATTCATAGAAGGGGGCTGGACCGGAATG ATTGACGGTTGGTACGGCTACCACCATCAAAACGAACAGGGGTCCGGATACGCCGCAGAC CAAAAAAGTACCCAAAATGCTATTAATGGCATAACCAATAAAGTCAACACGGTCATTGAA AAGATGAACATCCAGTTCACTGCTGTGGGAAAGGAGTTCAATAAGCTGGAGAAACGAATG GAGAACCTCAACAAAAAAGTAGATGACGGCTTTTTGGACATCTGGACCTACAATGCAGAG CTTCTGGTGCTATTAGAGAACGAACGTACATTAGACTTTCACGACTCCAACGTCAAAAAC CTGTATGAGAAGGTGAAATCCCAGCTTAAGAATAACGCAAAGGAAATCGGGAACGGCTGC TTTGAATTCTATCACAAGTGTGACAATGAGTGTATGGAGAGCGTGCGCAATGGGACCTAC GACTATCCTAAGTACTCAGAAGAGTCTAAACTGAACCGTGAAAAGGTCGACGGCGTTAAG CTGGAGTCTATGGGGATCTATCAGATCCTTGCAATTTATTCCACCGTGGCGTCTTCCTTG GTTTTGCTAGTGAGTTTAGGTGCTATCAGTTTCTGGATGTGCTCCAATGGCTCCCTGCAA TGTAGGATCTGCATT 465 ATGAAGGCCAACCTCCTGGTCTTGCTGTGCGCCCTGGCTGCTGCCGATGCAGATACCATT TGCATCGGCTATCACGCCAACAATTCTACAGATACCGTGGATACAGTACTCGAAAAAAAT GTTACTGTGACGCACTCAGTCAACCTGTTGGAAGACTCGCACAATGGCAAACTGTGCAGG CTGAAAGGCATTGCCCCCCTACAGCTGGGGAAGTGCAACATTGCAGGCTGGCTGTTGGGA AACCCTGAATGTGATCCATTGCTCCCAGTGCGGTCCTGGTCTTACATCGTGGAGACACCA AACAGCGAGAATGGGATCTGTTACCCTGGCGATTTTATAGACTACGAGGAGCTCAGGGAG CAGCTCAGCTCTGTGTCGTCTTTCGAGCGCTTTGAGATTTTTCCTAAGGAGTCCTCCTGG CCAAACCACAACACGAATGGAGTGACAGCCGCCTGTAGCCACGAGGGCAAGTCCTCATTC TATAGAAACTTGCTTTGGCTAACTGAAAAGGAGGGCAGCTACCCTAAACTGAAAAATAGC TATGTGAACAAAAAAGGCAAAGAAGTGCTCGTCCTGTGGGGGATCCATCATCCTCCTAAC TCAAAGGAGCAGCAGAACCTGTATCAGAATGAAAACGCTTACGTGTCTGTCGTGACTTCA AATTATAACCGGAGGTTCACTCCCGAAATTGCCGAGAGACCAAAGGTCAGGGACCAGGCA GGCCGCATGAATTACTATTGGACACTTCTGAAACCAGGCGACACAATTATTTTCGAGGCA AACGGGAACCTTATAGCCCCAATGTACGCCTTCGCACTATCAAGAGGCTTCGGTTCCGGC ATCATTACAAGCAACGCGAGCATGCATGAATGCAACACCAAGTGCCAAACCCCACTGGGT GCAATTAATAGTTCCCTGCCATATCAGAATATCCACCCGGTGACAATTGGAGAGTGCCCT AAGTACGTGAGGAGCGCTAAGTTAAGAATGGTGACGGGACTGAGAAACAACCCTTCCATT CAGTCCCGAGGACTTTTTGGAGCAATCGCCGGCTTTATTGAGGGGGGCTGGACGGGGATG ATTGATGGCTGGTATGGGTATCACCACCAGAATGAACAGGGAAGTGGGTACGCTGCTGAT CAGAAGTCAACTCAGAATGCCATCAACGGGATAACAAATAAGGTAAATACTGTGATTGAA AAAATGAATATCCAGTTCACTGCCGTTGGGAAGGAGTTTAACAAGCTTGAGAAAAGGATG GAAAACCTGAATAAGAAGGTAGATGACGGATTCCTCGATATATGGACCTACAACGCTGAG CTGCTGGTTTTGCTAGAGAACGAAAGAACTTTGGATTTTCATGATTCTAACGTGAAGAAC TTGTACGAAAAAGTGAAAAGTCAGCTTAAAAACAACGCAAAGGAGATTGGGAATGGCTGC TTTGAGTTTTATCACAAGTGCGACAATGAATGTATGGAGAGCGTGAGGAACGGCACGTAT GACTACCCCAAGTACAGTGAGGAATCCAAGCTGAACCGAGAAAAGGTCGACGGCGTGAAG CTGGAGTCTATGGGAATCTATCAGATTCTCGCAATTTACTCAACTGTCGCATCATCCCTA GTGCTCCTGGTGAGCCTGGGAGCCATTTCTTTCTGGATGTGTAGCAATGGTAGTTTACAA TGCAGAATCTGTATT 466 ATGAAGGCAAATCTGCTGGTCTTACTGTGCGCTCTGGCCGCTGCTGATGCTGATACAATC TGTATTGGCTACCACGCCAATAACTCCACTGATACAGTGGATACTGTGCTGGAAAAAAAT GTTACAGTCACACATTCAGTGAACCTCCTAGAAGACAGCCATAACGGAAAACTCTGCCGG CTGAAAGGTATCGCACCTTTGCAGCTAGGAAAGTGCAATATTGCGGGCTGGCTGCTTGGT AATCCCGAGTGCGACCCACTCTTACCAGTGAGAAGTTGGAGCTATATCGTAGAGACCCCC AACTCTGAGAATGGAATCTGTTATCCAGGCGACTTTATTGATTACGAGGAACTGCGCGAG CAACTCTCTTCTGTGTCTTCATTCGAGAGGTTTGAAATCTTCCCTAAGGAGTCGTCTTGG CCTAATCACAATACCAACGGGGTGACCGCCGCTTGCAGCCACGAGGGGAAGAGTTCTTTT TACCGAAATCTTCTGTGGCTAACAGAAAAGGAAGGATCATACCCAAAATTAAAGAATAGC TATGTAAACAAGAAGGGTAAGGAGGTTCTTGTCTTATGGGGCATACATCATCCCCCCAAC TCTAAGGAACAACAGAATCTATATCAGAACGAGAATGCTTACGTGAGTGTGGTGACCAGT AATTATAATAGAAGATTCACTCCTGAGATTGCCGAAAGGCCTAAAGTGCGCGACCAAGCG GGACGGATGAACTACTACTGGACCTTGCTCAAGCCGGGTGACACAATTATTTTTGAAGCA AATGGTAATCTCATTGCACCAATGTATGCGTTTGCCCTGAGTCGTGGATTTGGCAGCGGA ATAATAACTTCAAACGCCAGCATGCACGAATGCAATACTAAATGTCAGACCCCACTGGGG GCAATCAACTCCTCACTGCCATATCAGAACATCCACCCCGTGACCATTGGTGAGTGCCCT AAGTATGTTAGATCAGCGAAGCTTCGGATGGTAACAGGACTTAGAAATAATCCGAGCATT CAAAGCCGCGGGCTGTTTGGAGCCATTGCAGGGTTTATCGAAGGGGGTTGGACCGGCATG ATTGATGGCTGGTATGGATACCACCATCAGAACGAACAAGGCAGCGGGTATGCAGCTGAC CAAAAGTCTACCCAGAACGCCATCAATGGAATCACGAACAAGGTTAATACAGTGATTGAG AAGATGAATATTCAGTTTACAGCCGTTGGCAAGGAGTTCAACAAGCTGGAGAAGCGAATG GAGAACTTAAATAAAAAGGTCGACGACGGCTTCCTGGACATTTGGACATACAACGCTGAA CTGTTGGTGCTTCTCGAGAATGAACGAACTTTAGATTTTCACGATAGCAACGTTAAAAAC TTATATGAGAAAGTGAAGTCTCAGCTCAAGAATAATGCCAAGGAGATAGGTAATGGTTGC TTCGAATTCTATCACAAGTGTGACAACGAATGCATGGAGAGTGTTAGAAACGGTACATAC GATTATCCCAAGTATAGTGAGGAGTCCAAACTCAATAGGGAAAAGGTGGACGGGGTGAAG CTCGAGAGCATGGGCATTTATCAGATCCTTGCAATATACTCAACCGTAGCATCTTCTCTC GTTCTTCTGGTGTCCCTGGGCGCTATTTCTTTTTGGATGTGCAGTAATGGCAGCCTTCAA TGTAGAATTTGCATC 467 ATGAAGGCCAATCTCCTGGTGCTTCTATGTGCACTGGCCGCGGCCGATGCCGACACCATT TGCATTGGCTATCACGCCAATAATTCCACTGACACAGTTGATACCGTGCTCGAAAAAAAC GTAACCGTGACCCATTCCGTTAACCTGCTTGAGGATTCTCACAACGGGAAACTCTGCAGA CTGAAGGGCATCGCCCCCCTGCAGCTGGGAAAATGCAATATTGCCGGCTGGCTCTTAGGT AACCCAGAATGTGATCCATTACTGCCGGTCAGAAGCTGGAGCTACATCGTGGAAACCCCC AACTCTGAGAATGGAATCTGTTATCCCGGAGATTTTATTGATTACGAGGAGCTCCGCGAA CAGCTATCCTCTGTATCTTCTTTTGAGAGATTCGAGATTTTCCCCAAGGAGAGCAGCTGG CCAAACCACAACACTAATGGTGTCACCGCCGCCTGCTCCCATGAAGGAAAGTCCAGCTTT TATCGGAACTTACTGTGGCTGACAGAGAAGGAGGGCTCTTACCCCAAGCTGAAGAACAGC TATGTCAATAAAAAGGGCAAGGAAGTCCTAGTGTTGTGGGGGATCCACCATCCACCTAAC AGCAAAGAGCAGCAGAACCTCTACCAGAATGAGAATGCGTACGTTTCTGTGGTGACTTCA AACTATAACCGCCGATTCACACCCGAGATCGCAGAGAGACCTAAAGTCAGGGACCAAGCG GGGAGAATGAACTACTACTGGACCCTCTTGAAGCCCGGCGATACCATTATTTTTGAGGCT AACGGCAACCTGATCGCCCCCATGTATGCATTCGCTCTGAGCCGTGGCTTCGGATCTGGT ATTATAACCTCAAACGCAAGCATGCATGAATGTAACACCAAATGCCAGACCCCCCTGGGG GCCATCAACAGCAGTCTGCCATACCAGAACATCCACCCTGTCACCATTGGTGAATGCCCC AAGTATGTCCGATCAGCGAAACTGCGGATGGTCACGGGGCTGCGAAACAATCCTTCAATC CAGAGCCGAGGACTTTTTGGAGCTATCGCCGGATTCATTGAAGGCGGCTGGACAGGGATG ATCGACGGTTGGTACGGGTATCACCACCAGAACGAGCAAGGCAGTGGCTACGCAGCTGAC CAGAAATCCACCCAAAACGCCATTAACGGGATCACTAACAAAGTGAACACGGTCATCGAG AAGATGAATATTCAATTCACTGCCGTTGGCAAAGAGTTTAATAAGTTGGAAAAGCGCATG GAGAATCTAAACAAAAAGGTTGACGATGGTTTCTTGGATATCTGGACATATAATGCCGAG CTGTTAGTCCTGTTAGAAAACGAGAGAACCCTTGATTTTCATGATAGCAACGTCAAAAAC TTATACGAGAAGGTGAAAAGCCAGCTTAAAAATAATGCCAAAGAGATAGGAAATGGCTGT TTTGAGTTCTATCATAAGTGCGATAACGAGTGCATGGAGTCCGTTCGGAATGGTACCTAC GATTACCCGAAGTACTCTGAGGAGAGCAAGTTGAATCGGGAGAAAGTTGATGGCGTCAAG CTCGAATCCATGGGTATCTACCAGATATTAGCTATTTACTCCACAGTCGCATCTAGCCTG GTCCTGCTGGTTTCGCTGGGCGCCATATCTTTTTGGATGTGTTCTAATGGCAGCTTACAA TGCAGGATTTGTATC 468 ATGAAAGCCAACCTCCTCGTGTTGCTGTGCGCTTTGGCCGCTGCCGACGCCGACACCATC TGTATAGGCTATCATGCGAATAATAGCACCGACACAGTAGATACCGTTCTGGAGAAGAAC GTGACCGTGACTCACAGCGTGAATCTGTTGGAGGACTCCCATAATGGGAAGCTGTGTAGA TTGAAAGGTATTGCACCGCTACAACTCGGGAAGTGCAATATCGCCGGGTGGCTGCTTGGT AACCCCGAGTGTGACCCACTGCTGCCAGTTCGTTCTTGGAGTTACATCGTGGAGACTCCT AATAGCGAGAATGGTATCTGCTACCCTGGGGACTTCATCGATTATGAGGAGCTCAGAGAG CAGTTGAGTTCCGTGTCATCATTTGAGCGGTTTGAGATTTTTCCAAAGGAAAGTTCGTGG CCGAACCATAACACTAACGGAGTCACCGCCGCCTGTAGTCACGAGGGCAAATCTTCTTTT TACCGGAATTTGCTGTGGCTTACAGAAAAAGAGGGCTCCTATCCGAAGCTGAAGAACTCT TATGTGAATAAAAAAGGAAAGGAAGTCCTAGTGCTGTGGGGAATCCATCATCCTCCAAAT AGTAAGGAGCAGCAGAACCTATATCAGAACGAGAACGCATACGTGTCCGTGGTCACGTCA AACTACAACCGGAGGTTCACTCCCGAGATCGCCGAAAGGCCTAAGGTTCGGGATCAGGCT GGGCGCATGAACTACTACTGGACTTTACTGAAACCAGGAGACACCATTATCTTCGAGGCT AACGGCAATCTCATAGCTCCGATGTACGCCTTTGCCTTGAGTCGCGGATTCGGAAGTGGT ATCATTACTAGCAATGCCTCAATGCATGAGTGTAACACAAAATGCCAGACCCCCTTGGGA GCAATTAACTCATCTCTACCATATCAGAACATCCACCCTGTCACTATAGGGGAGTGTCCC AAGTATGTCAGATCCGCCAAGTTGCGGATGGTAACCGGGCTGCGGAATAACCCCTCCATC CAGTCCCGTGGCCTTTTTGGCGCCATTGCGGGATTTATTGAGGGAGGCTGGACGGGCATG ATTGATGGCTGGTATGGTTATCACCACCAGAATGAACAGGGGTCTGGTTATGCTGCCGAC CAGAAGAGTACCCAAAACGCCATCAATGGAATTACAAACAAGGTGAATACAGTGATCGAA AAAATGAACATCCAGTTTACTGCAGTTGGTAAAGAATTCAACAAACTAGAAAAGCGGATG GAGAACCTCAACAAGAAGGTCGATGACGGCTTTCTGGACATCTGGACATACAACGCCGAA CTTCTAGTGCTTCTGGAGAATGAGCGCACACTGGATTTTCACGACTCAAATGTTAAGAAC CTCTACGAAAAGGTGAAGTCCCAGCTCAAAAACAACGCCAAGGAGATTGGCAATGGCTGT TTTGAATTTTACCACAAATGCGACAATGAATGTATGGAGTCCGTCCGGAATGGCACCTAT GACTATCCAAAGTATTCTGAGGAATCCAAGCTGAATCGGGAAAAAGTGGATGGTGTGAAA CTTGAGTCAATGGGAATTTATCAGATCCTGGCCATTTACAGTACGGTGGCCTCCTCACTG GTGCTACTGGTAAGTCTGGGAGCAATTTCATTCTGGATGTGCTCCAATGGTTCACTGCAG TGCAGAATCTGCATA 469 ATGAAGGCTAACCTGCTGGTACTTCTGTGTGCGCTCGCGGCAGCTGATGCCGACACGATC TGTATTGGATATCATGCGAACAATAGCACAGACACCGTGGATACAGTTCTGGAAAAGAAC GTGACTGTCACGCACTCCGTCAACTTACTAGAGGACTCTCACAACGGGAAGCTCTGCAGA CTGAAGGGAATTGCACCCTTGCAGCTGGGTAAGTGTAACATCGCTGGATGGCTACTTGGT AACCCCGAGTGTGACCCTCTCCTGCCCGTGCGGTCCTGGAGCTACATAGTTGAGACACCA AACTCTGAGAACGGGATCTGCTATCCTGGGGACTTCATTGACTACGAGGAGCTGCGGGAG CAGCTCTCCTCCGTCTCGTCTTTCGAAAGGTTCGAGATTTTCCCAAAAGAATCAAGTTGG CCCAACCACAACACAAATGGTGTTACCGCCGCCTGTAGCCATGAAGGGAAATCAAGCTTC TACCGTAATCTGCTTTGGCTTACCGAAAAAGAAGGAAGCTACCCTAAGTTAAAAAACTCT TATGTCAACAAAAAAGGGAAAGAAGTTTTGGTGCTGTGGGGCATCCACCACCCTCCTAAT TCGAAAGAACAGCAGAACTTGTATCAGAACGAAAATGCCTACGTGTCCGTGGTGACCAGT AACTACAACCGACGGTTCACCCCGGAGATAGCAGAGAGGCCAAAAGTCAGAGATCAGGCT GGCAGAATGAACTATTACTGGACCCTCCTAAAACCCGGAGACACTATTATATTTGAGGCA AATGGTAATCTGATCGCTCCAATGTATGCTTTCGCCCTCTCCCGCGGATTCGGGTCAGGG ATAATCACCTCTAACGCTTCTATGCACGAATGTAACACCAAGTGCCAAACTCCCCTTGGA GCCATCAACAGTTCTCTACCATACCAGAATATCCATCCAGTGACGATCGGCGAATGCCCT AAATACGTCAGAAGTGCTAAGCTAAGAATGGTTACTGGGCTGAGAAATAATCCGTCCATT CAGAGCAGGGGGCTGTTTGGAGCGATCGCTGGATTTATTGAAGGAGGTTGGACCGGGATG ATCGATGGCTGGTACGGTTATCACCATCAAAATGAGCAGGGAAGCGGATACGCCGCAGAC CAGAAAAGCACACAGAACGCTATTAACGGAATCACTAATAAGGTGAATACTGTCATCGAG AAAATGAACATTCAGTTCACAGCAGTGGGCAAAGAGTTTAACAAGCTTGAAAAGAGGATG GAGAATCTCAACAAGAAGGTGGATGACGGCTTCCTCGACATCTGGACTTATAACGCCGAG CTCCTCGTCCTGCTCGAAAATGAAAGGACTTTGGACTTCCACGATTCAAACGTGAAGAAT TTGTACGAAAAGGTGAAGTCCCAGCTGAAAAACAACGCTAAGGAGATAGGGAATGGCTGT TTCGAATTCTACCACAAGTGCGACAATGAGTGCATGGAGAGTGTTAGAAATGGGACGTAT GACTATCCTAAGTATTCGGAGGAATCAAAGTTGAATCGAGAGAAGGTGGACGGTGTGAAG TTAGAGTCGATGGGCATCTACCAGATTCTGGCTATCTATTCCACCGTGGCTAGCAGCTTG GTCCTCCTCGTATCATTGGGCGCAATTAGCTTCTGGATGTGCTCCAACGGTTCCCTTCAG TGCAGAATCTGTATC 470 ATGAAAGCAAATCTGCTGGTGCTGTTGTGCGCGCTGGCGGCTGCTGACGCAGACACCATT TGCATCGGCTACCACGCCAACAACAGTACTGATACTGTGGACACAGTTTTAGAAAAGAAT GTGACCGTAACACATAGCGTAAACTTGCTGGAAGACAGTCACAATGGAAAACTCTGCCGG CTGAAGGGAATCGCCCCTCTACAGCTCGGCAAATGCAATATCGCCGGGTGGCTATTGGGG AATCCAGAGTGCGACCCACTTCTGCCTGTGCGCAGTTGGTCATATATCGTGGAAACACCA AACTCCGAAAACGGCATTTGCTATCCTGGAGACTTTATTGACTACGAAGAGCTAAGAGAG CAGCTGAGCTCCGTGTCCAGTTTTGAGCGATTTGAGATCTTCCCAAAGGAGAGCTCTTGG CCAAATCACAATACCAACGGAGTGACCGCGGCTTGTTCTCACGAGGGTAAATCCTCCTTT TATAGGAACCTGCTGTGGCTGACCGAGAAAGAGGGATCTTACCCAAAACTTAAGAACAGC TATGTTAACAAGAAGGGAAAAGAAGTGCTTGTGCTGTGGGGTATTCACCACCCTCCTAAT TCCAAGGAGCAGCAGAATCTGTATCAGAATGAGAATGCCTACGTCAGCGTGGTCACCTCA AATTATAACAGACGGTTCACCCCAGAGATTGCGGAGCGTCCCAAGGTAAGGGACCAAGCC GGACGCATGAACTATTATTGGACTCTGCTGAAACCTGGTGATACTATCATCTTTGAGGCC AATGGCAATCTTATCGCCCCTATGTATGCATTTGCCCTATCTCGCGGATTTGGGAGCGGC ATCATCACAAGTAATGCCAGCATGCACGAATGTAATACCAAATGCCAGACACCTCTGGGC GCTATCAACAGCAGCCTGCCTTATCAGAATATACACCCTGTCACCATCGGGGAATGCCCT AAATATGTTCGCAGTGCCAAACTTCGTATGGTGACTGGGCTGCGCAACAACCCATCAATT CAGAGCAGGGGCCTGTTCGGAGCGATTGCCGGGTTTATCGAGGGAGGGTGGACGGGCATG ATAGATGGCTGGTACGGATACCACCATCAAAATGAACAGGGCAGTGGCTACGCAGCGGAC CAGAAATCCACCCAGAATGCTATAAACGGTATCACAAATAAGGTGAATACAGTCATCGAA AAGATGAATATTCAGTTCACTGCGGTCGGTAAGGAGTTCAACAAACTGGAGAAGAGGATG GAAAATCTTAACAAAAAAGTGGACGACGGCTTCCTGGATATATGGACGTATAATGCAGAA CTGTTAGTGTTACTCGAGAATGAGAGGACTCTCGACTTCCATGATTCCAACGTGAAGAAT CTCTATGAGAAGGTGAAATCCCAACTGAAGAACAACGCCAAAGAGATAGGGAATGGATGC TTCGAATTCTACCATAAGTGTGATAACGAGTGTATGGAGTCTGTGCGGAATGGCACTTAC GACTATCCGAAATACAGTGAGGAGTCAAAGTTGAACCGGGAGAAGGTCGATGGCGTCAAG CTGGAGAGTATGGGAATCTATCAGATCCTCGCAATTTACTCAACCGTGGCTAGCTCCCTG GTACTCCTGGTCTCACTTGGAGCCATCTCCTTCTGGATGTGCAGCAACGGCAGCCTTCAG TGCAGAATCTGCATT 471 ATGAAGGCCAATCTTTTAGTGCTGTTGTGTGCACTGGCGGCAGCTGATGCTGACACCATC TGCATCGGATACCACGCCAATAACAGCACTGACACAGTTGACACTGTTCTGGAAAAAAAC GTGACGGTGACCCACTCCGTCAATCTTCTGGAGGACTCCCACAACGGGAAGCTGTGTAGG TTGAAGGGTATCGCCCCGTTGCAGCTGGGCAAATGCAACATCGCGGGTTGGCTGCTTGGC AATCCTGAGTGCGATCCACTGCTACCCGTACGGTCTTGGTCATATATCGTTGAGACCCCA AATAGCGAGAATGGCATCTGTTATCCTGGCGATTTCATCGACTACGAAGAGCTGCGAGAA CAACTGAGTTCGGTGTCTAGTTTCGAGAGGTTTGAGATCTTCCCAAAAGAAAGTTCCTGG CCTAACCACAATACCAACGGGGTAACGGCCGCTTGTAGCCACGAGGGCAAATCAAGCTTT TACAGAAATCTGCTGTGGCTCACAGAAAAAGAAGGGAGCTATCCTAAATTAAAGAATTCA TACGTGAACAAAAAAGGAAAGGAAGTACTCGTCCTGTGGGGAATTCACCACCCTCCAAAT TCTAAAGAACAACAGAACTTGTACCAGAATGAAAACGCCTATGTATCCGTGGTTACCTCA AACTACAATCGGCGGTTCACCCCCGAAATAGCTGAGAGACCGAAGGTTCGGGACCAAGCG GGAAGAATGAACTATTACTGGACTCTCCTTAAGCCCGGTGATACTATCATCTTTGAAGCC AACGGAAACCTTATCGCCCCAATGTATGCCTTCGCGTTATCCCGCGGGTTTGGAAGCGGT ATTATTACTTCAAACGCGAGCATGCACGAATGTAATACTAAATGTCAGACACCCCTTGGC GCCATCAATAGCAGTCTGCCATACCAAAATATTCACCCCGTGACAATTGGCGAGTGTCCA AAATATGTTAGAAGCGCCAAACTCAGAATGGTTACTGGCTTGCGGAATAACCCGTCCATT CAGTCCAGAGGGTTATTTGGGGCAATCGCCGGCTTTATAGAAGGGGGCTGGACTGGAATG ATCGACGGTTGGTACGGATATCATCACCAGAATGAACAGGGATCAGGATATGCCGCGGAC CAAAAGTCTACCCAGAACGCCATCAACGGCATCACTAATAAGGTCAACACTGTGATTGAG AAGATGAATATTCAGTTCACCGCAGTCGGCAAGGAATTCAACAAACTCGAGAAACGCATG GAAAACCTTAACAAAAAGGTGGACGATGGGTTTCTGGACATTTGGACCTACAATGCCGAG CTGCTAGTGCTGCTGGAAAACGAGCGGACTCTTGATTTCCATGACTCTAATGTAAAAAAC CTTTACGAAAAAGTTAAATCACAACTTAAAAATAATGCCAAAGAAATAGGGAACGGATGT TTCGAGTTCTACCACAAATGTGATAACGAATGCATGGAGAGTGTTCGCAACGGAACATAT GACTATCCTAAGTACAGCGAAGAGTCAAAACTAAATCGGGAGAAAGTCGACGGCGTGAAA CTCGAATCCATGGGGATTTACCAGATCCTCGCAATCTATTCTACCGTGGCTAGCTCGCTG GTGCTGCTTGTTAGTCTGGGAGCTATCTCCTTTTGGATGTGTAGCAATGGAAGCCTGCAG TGTAGAATTTGCATA 472 ATGAAGGCCAACCTGCTGGTCCTGCTGTGTGCACTCGCCGCCGCCGATGCCGACACTATT TGTATTGGCTACCACGCTAACAACTCCACAGATACAGTCGATACTGTGCTGGAAAAGAAT GTTACCGTCACCCATAGCGTGAACTTGCTCGAGGATTCTCATAATGGGAAACTCTGTCGG TTAAAGGGGATTGCACCTCTCCAACTGGGCAAGTGTAACATCGCGGGTTGGCTGCTTGGA AACCCTGAGTGCGATCCTCTACTTCCGGTCAGGTCGTGGAGTTACATTGTCGAGACCCCT AACTCAGAAAACGGTATCTGTTATCCGGGTGATTTTATCGATTACGAAGAGCTCAGAGAA CAGCTGTCCAGCGTGTCTTCATTCGAGCGATTCGAAATTTTCCCGAAGGAATCATCTTGG CCAAATCATAATACTAACGGGGTGACGGCCGCATGTTCACATGAGGGCAAATCCAGCTTC TACCGAAACCTTTTGTGGTTGACGGAGAAGGAGGGCTCTTATCCCAAGCTGAAAAACAGC TATGTGAACAAGAAGGGGAAGGAGGTGCTCGTTCTGTGGGGGATCCATCACCCTCCTAAC AGCAAAGAGCAGCAAAACCTGTATCAGAATGAAAACGCCTATGTGTCCGTGGTGACGAGC AACTACAACCGGCGCTTTACCCCCGAAATTGCTGAACGGCCGAAGGTGAGGGATCAAGCC GGCCGGATGAATTATTACTGGACGCTGCTGAAACCTGGTGATACCATCATCTTTGAAGCT AACGGAAACTTGATCGCTCCAATGTATGCATTCGCCCTGTCACGGGGATTCGGCAGCGGT ATAATCACCAGTAATGCCTCAATGCACGAATGCAATACCAAGTGCCAAACGCCCCTTGGT GCCATCAACTCATCTCTGCCCTATCAGAATATCCATCCTGTAACCATCGGAGAGTGTCCC AAGTATGTCAGATCAGCAAAACTGCGGATGGTCACAGGTCTCCGAAATAATCCCTCAATC CAGTCTCGCGGCCTGTTCGGCGCTATCGCCGGCTTTATTGAGGGCGGTTGGACCGGGATG ATCGACGGCTGGTATGGATACCATCATCAGAACGAGCAGGGGAGCGGCTACGCGGCTGAC CAGAAGTCAACCCAGAATGCTATCAATGGTATCACTAATAAGGTGAATACGGTGATTGAA AAAATGAACATACAGTTCACCGCAGTGGGTAAAGAGTTCAATAAGCTGGAGAAGCGGATG GAGAATCTGAACAAAAAGGTCGATGATGGCTTCTTGGACATCTGGACCTATAACGCCGAG CTTCTTGTGCTGCTCGAGAACGAGAGAACACTGGACTTCCATGACTCTAACGTGAAGAAC CTCTACGAGAAGGTGAAATCTCAGTTGAAGAACAACGCTAAGGAGATCGGCAATGGCTGC TTCGAATTCTACCACAAGTGCGATAACGAATGCATGGAATCTGTTCGAAATGGAACTTAC GATTACCCTAAATACAGCGAGGAAAGTAAGTTAAACAGAGAGAAAGTAGACGGGGTTAAG CTCGAAAGCATGGGGATCTATCAGATCCTAGCCATCTACTCGACTGTCGCGTCAAGTTTG GTGCTGCTGGTGTCTCTTGGAGCCATATCGTTTTGGATGTGCTCTAACGGCTCCCTGCAG TGCAGAATCTGCATA 473 ATGAAGGCCAACTTGCTAGTGCTGCTGTGCGCGCTTGCAGCTGCGGATGCGGATACGATA TGCATAGGATATCACGCCAATAATTCGACGGATACCGTGGACACAGTGCTGGAAAAGAAT GTAACGGTCACACACAGCGTGAACCTGCTTGAAGATTCACACAACGGCAAACTGTGCAGG CTCAAAGGAATCGCACCATTACAGCTGGGGAAATGCAACATTGCGGGGTGGCTGCTAGGA AACCCAGAGTGCGATCCCCTGCTGCCCGTGCGGTCTTGGTCCTACATTGTAGAGACTCCG AACTCGGAGAACGGTATTTGCTACCCTGGAGATTTCATTGACTATGAAGAACTCAGGGAG CAACTGTCCTCAGTTTCGAGCTTTGAAAGGTTCGAGATCTTTCCTAAGGAGTCCAGCTGG CCTAACCACAATACAAACGGGGTGACCGCGGCCTGTTCACATGAGGGTAAATCTTCATTC TACCGCAACCTCCTGTGGTTAACCGAAAAAGAAGGAAGCTATCCTAAGCTGAAGAATTCT TACGTGAATAAAAAGGGTAAGGAAGTTCTGGTGCTGTGGGGCATCCACCACCCACCTAAT AGTAAGGAACAGCAGAACCTATACCAGAACGAAAATGCGTACGTGAGCGTGGTAACTTCA AACTATAATCGGAGGTTCACACCCGAAATCGCGGAGCGGCCCAAGGTGCGGGACCAGGCT GGGCGCATGAATTATTACTGGACACTGTTGAAACCTGGAGACACTATAATCTTCGAGGCG AACGGAAACTTAATCGCTCCCATGTACGCATTCGCCCTGTCCCGTGGCTTTGGCAGCGGT ATCATCACATCCAACGCCTCTATGCACGAATGCAATACGAAGTGCCAAACCCCTCTCGGA GCCATTAATAGCTCCCTCCCATATCAGAACATTCACCCAGTGACCATAGGAGAGTGTCCT AAGTACGTTCGGAGCGCAAAACTCCGCATGGTGACGGGGTTGCGAAACAACCCTTCCATC CAGTCGAGGGGCCTTTTCGGGGCGATCGCTGGCTTCATCGAGGGAGGGTGGACCGGGATG ATTGACGGCTGGTACGGGTATCACCACCAGAACGAGCAGGGTAGCGGCTACGCCGCAGAC CAGAAATCTACGCAGAATGCCATTAATGGGATTACAAACAAGGTTAATACCGTGATCGAG AAAATGAACATTCAGTTCACAGCCGTCGGCAAAGAATTTAACAAATTAGAGAAGCGGATG GAGAATCTGAATAAAAAAGTGGACGATGGATTCCTGGATATCTGGACGTATAATGCCGAG TTGCTCGTCCTTCTGGAAAACGAGAGAACCCTGGACTTTCACGATTCAAATGTAAAGAAC CTTTACGAAAAGGTGAAGTCTCAACTGAAAAACAACGCCAAGGAGATAGGGAATGGCTGC TTTGAATTCTACCATAAATGCGACAATGAATGTATGGAGTCTGTTAGGAATGGTACTTAC GACTACCCGAAGTATTCCGAAGAGAGCAAGCTGAATAGGGAGAAGGTGGATGGAGTGAAA CTGGAATCTATGGGGATTTATCAGATCCTAGCTATTTATTCTACAGTAGCCAGCTCCCTC GTCCTTCTGGTCTCCCTGGGCGCAATTTCATTTTGGATGTGCAGCAACGGGTCCTTACAA TGCCGCATCTGTATT 474 ATGAAGGCTAACCTGCTTGTGTTATTGTGCGCCCTGGCGGCAGCAGACGCAGATACCATA TGTATCGGGTATCACGCTAATAATAGCACTGACACCGTTGACACCGTCCTGGAAAAAAAC GTGACCGTGACTCATTCAGTTAATCTTTTGGAGGACAGCCATAATGGCAAGCTTTGTAGA CTCAAGGGCATCGCACCTTTACAGTTGGGTAAGTGCAACATCGCAGGATGGCTCCTTGGC AACCCTGAATGTGACCCGCTGCTCCCAGTCCGGAGTTGGTCATATATCGTAGAAACTCCC AATAGCGAAAACGGCATTTGCTACCCAGGCGACTTTATAGATTACGAAGAGCTCCGGGAG CAGCTATCAAGTGTCTCGTCGTTTGAGCGTTTTGAGATTTTTCCGAAAGAATCCAGTTGG CCAAATCACAACACAAACGGTGTAACAGCGGCTTGTTCACACGAGGGTAAAAGTTCTTTC TACAGAAATTTATTGTGGCTTACAGAGAAAGAAGGCTCTTACCCAAAGCTGAAGAATTCT TATGTGAACAAGAAGGGTAAGGAGGTGTTAGTACTGTGGGGAATACATCACCCTCCTAAT AGCAAGGAGCAGCAGAACTTGTATCAGAACGAAAACGCATATGTGTCTGTGGTGACATCC AATTATAATAGGCGTTTTACTCCCGAAATTGCAGAGCGACCTAAAGTGCGTGACCAGGCA GGTAGAATGAATTACTACTGGACCCTGTTGAAGCCCGGTGACACCATCATTTTCGAAGCA AATGGTAACCTGATCGCACCAATGTACGCATTTGCACTGTCCCGCGGATTTGGCTCCGGA ATCATTACCAGTAATGCCTCTATGCATGAATGTAACACCAAATGCCAGACCCCCCTGGGC GCCATTAACTCCAGCCTGCCTTATCAGAATATACATCCTGTGACAATAGGTGAGTGCCCC AAGTACGTGAGATCTGCAAAACTAAGAATGGTCACCGGACTCAGGAACAATCCCTCCATC CAGAGTAGGGGTCTGTTCGGAGCCATAGCAGGGTTCATTGAAGGTGGATGGACAGGGATG ATCGATGGATGGTACGGCTACCACCACCAGAATGAGCAGGGCTCTGGCTACGCCGCTGAC CAGAAATCTACACAGAACGCCATTAATGGCATCACTAACAAAGTGAATACCGTCATTGAG AAGATGAATATTCAGTTCACTGCCGTTGGCAAGGAATTTAACAAACTGGAGAAGCGGATG GAGAATCTAAATAAGAAAGTAGACGACGGGTTTCTCGATATTTGGACATATAACGCTGAG CTTCTAGTCCTACTCGAGAACGAGAGGACCCTCGACTTCCATGATAGCAACGTGAAGAAC CTATACGAGAAGGTCAAGTCTCAACTGAAGAACAACGCTAAGGAGATCGGAAATGGATGT TTCGAGTTTTATCACAAGTGTGATAACGAGTGTATGGAGTCTGTAAGGAACGGTACCTAT GACTACCCAAAATACAGCGAGGAATCAAAGCTCAATCGTGAGAAAGTCGATGGAGTTAAG CTGGAATCTATGGGGATTTATCAGATCTTAGCTATCTATTCAACCGTTGCTTCCAGCTTA GTCCTCCTCGTGTCACTGGGGGCTATAAGTTTTTGGATGTGCAGTAATGGCAGTTTGCAG TGTAGGATCTGCATC 475 ATGAAGGCTAATTTATTGGTGCTGTTGTGTGCACTGGCTGCCGCAGACGCCGACACCATC TGCATTGGATATCATGCCAACAATTCAACTGATACGGTCGATACGGTGCTTGAGAAAAAT GTGACAGTTACACACTCTGTGAACCTTCTGGAAGACTCTCATAACGGCAAACTTTGTCGG TTGAAGGGTATCGCCCCACTGCAGCTTGGTAAGTGCAACATCGCCGGTTGGCTCCTCGGA AATCCAGAGTGTGATCCACTGTTACCTGTGCGTAGTTGGAGTTACATCGTGGAGACTCCT AATAGTGAAAACGGCATATGCTATCCAGGCGATTTCATCGATTATGAAGAACTGCGTGAG CAGCTGTCCAGCGTGTCCTCATTCGAGCGCTTTGAGATCTTCCCGAAAGAGTCCAGTTGG CCAAACCACAATACCAATGGGGTCACTGCCGCCTGTAGTCATGAGGGTAAAAGCTCCTTC TATCGGAATCTTCTCTGGCTGACCGAAAAAGAAGGGTCCTACCCCAAACTTAAGAATTCG TACGTCAACAAGAAGGGCAAAGAAGTACTTGTGCTGTGGGGTATCCACCACCCTCCCAAC TCTAAGGAGCAGCAGAATCTGTACCAGAATGAGAACGCTTACGTCAGCGTGGTGACCTCA AATTATAACCGAAGGTTCACTCCCGAGATAGCCGAGCGGCCTAAGGTCAGAGACCAAGCG GGTAGAATGAATTACTACTGGACACTACTAAAGCCCGGCGACACCATCATCTTTGAGGCA AATGGAAATCTGATCGCCCCCATGTATGCATTTGCACTGAGCCGGGGGTTCGGATCTGGA ATCATAACTTCAAACGCCAGTATGCATGAATGCAATACAAAGTGTCAGACTCCCTTGGGT GCCATCAATTCCAGCCTGCCTTATCAGAATATCCACCCTGTGACAATTGGAGAGTGCCCA AAATACGTTCGTTCAGCTAAACTGAGAATGGTCACCGGCCTCCGGAACAATCCTAGTATA CAGTCACGCGGCCTTTTCGGCGCCATTGCCGGATTTATTGAAGGAGGCTGGACAGGCATG ATAGACGGATGGTACGGATATCACCACCAGAACGAACAAGGGTCTGGCTATGCCGCAGAC CAGAAATCCACCCAGAACGCTATCAATGGTATCACGAATAAAGTCAATACCGTCATCGAG AAGATGAATATCCAGTTTACAGCTGTGGGAAAAGAGTTCAATAAGCTTGAAAAGAGGATG GAGAACCTGAATAAAAAAGTTGATGACGGATTTCTCGACATCTGGACGTATAACGCTGAA CTGCTTGTGCTGCTCGAAAACGAGAGGACATTGGATTTTCACGACTCCAATGTTAAGAAT CTGTACGAGAAGGTGAAATCTCAGCTCAAGAATAATGCTAAGGAAATAGGCAACGGATGT TTCGAATTTTATCATAAGTGCGACAATGAATGCATGGAATCAGTGCGCAACGGGACCTAT GACTACCCCAAGTACAGCGAGGAGTCCAAGCTGAATAGAGAAAAGGTGGACGGCGTCAAA CTGGAAAGTATGGGCATTTACCAAATTCTCGCCATCTACTCTACCGTTGCCAGCAGTCTC GTGCTGTTAGTATCACTCGGTGCCATCTCTTTTTGGATGTGTAGTAATGGAAGCCTGCAG TGCCGGATCTGTATC 476 ATGAAGGCCAACCTGCTCGTGTTGCTGTGTGCACTAGCTGCCGCCGACGCAGACACCATC TGTATCGGCTACCATGCCAACAACAGCACCGACACAGTGGATACGGTGCTCGAGAAGAAC GTGACTGTCACCCATAGTGTGAATCTCCTAGAGGATTCTCATAATGGGAAGCTATGCCGA CTCAAGGGGATTGCACCTCTGCAACTGGGTAAGTGCAATATCGCCGGTTGGCTTCTTGGG AACCCCGAATGTGATCCCCTGCTCCCCGTGCGATCTTGGTCATATATCGTTGAAACACCC AATAGCGAAAATGGCATATGCTACCCTGGAGATTTCATTGACTATGAGGAACTCCGAGAA CAGCTGTCAAGCGTGTCTAGTTTCGAACGGTTTGAAATATTCCCTAAGGAGAGTTCCTGG CCCAACCATAACACAAACGGAGTGACCGCAGCCTGCTCTCATGAGGGGAAGTCCTCATTT TATCGCAATCTCCTGTGGCTCACTGAAAAGGAGGGAAGTTACCCAAAATTGAAAAACTCA TACGTGAATAAGAAAGGCAAGGAGGTCCTCGTGCTGTGGGGGATTCATCACCCCCCTAAC TCAAAAGAACAGCAGAACCTGTATCAGAACGAAAACGCCTACGTGAGTGTGGTGACCTCT AACTATAACCGGAGGTTCACGCCAGAGATTGCTGAAAGACCTAAAGTCAGGGACCAAGCC GGCAGAATGAATTACTATTGGACCCTGTTGAAGCCCGGCGATACCATTATATTCGAGGCA AACGGCAACCTGATTGCCCCCATGTACGCGTTCGCCCTGAGTCGAGGCTTCGGCAGTGGG ATTATTACCTCTAACGCCTCGATGCATGAGTGCAACACAAAATGTCAAACTCCACTTGGG GCCATCAACTCGTCTCTTCCTTACCAAAATATCCACCCGGTTACAATTGGGGAATGTCCC AAATACGTGCGGTCCGCAAAGCTTCGCATGGTCACGGGCCTGAGGAACAACCCCTCTATC CAGTCTCGCGGTCTATTTGGCGCTATTGCTGGCTTTATCGAGGGGGGGTGGACAGGGATG ATTGATGGCTGGTACGGGTACCATCACCAAAATGAACAGGGGTCCGGCTATGCTGCTGAC CAAAAATCTACTCAAAACGCCATTAATGGAATCACAAATAAAGTGAATACGGTCATAGAA AAGATGAACATTCAATTTACAGCCGTGGGTAAGGAGTTCAACAAACTGGAGAAGCGAATG GAGAACTTAAACAAAAAGGTAGATGATGGTTTCCTCGATATCTGGACATATAATGCTGAG TTGTTGGTGCTCTTGGAGAATGAGCGGACCTTAGATTTCCACGACAGCAATGTTAAAAAC CTCTATGAAAAGGTGAAAAGTCAACTGAAGAACAATGCGAAAGAGATCGGTAACGGGTGC TTCGAGTTCTACCACAAATGCGACAACGAGTGTATGGAGAGTGTAAGGAATGGTACATAT GATTATCCTAAATACTCTGAAGAGTCGAAGCTGAACAGAGAGAAAGTCGACGGCGTAAAG CTGGAGAGTATGGGTATCTACCAAATCTTGGCCATCTATTCTACCGTGGCGTCATCACTA GTTCTTCTGGTGTCCTTGGGGGCCATATCATTCTGGATGTGTTCAAACGGGTCCCTCCAG TGCCGCATCTGCATC 477 ATGAAGGCAAACCTGTTGGTATTGTTGTGTGCCCTGGCAGCTGCGGATGCAGACACTATT TGCATCGGCTATCATGCAAATAATTCCACGGACACAGTTGACACCGTTCTGGAGAAAAAT GTGACGGTCACTCATTCTGTGAACCTGCTGGAAGACTCTCATAACGGAAAGCTGTGCCGG TTGAAGGGAATTGCACCACTACAACTGGGAAAATGCAACATCGCCGGCTGGTTGCTAGGT AACCCTGAGTGCGATCCACTCCTTCCAGTGAGATCCTGGTCCTACATCGTCGAGACCCCA AACTCAGAGAACGGGATCTGTTATCCAGGAGATTTCATTGACTATGAAGAGTTACGTGAA CAGCTCTCTTCCGTGTCGTCATTCGAACGGTTTGAAATCTTCCCCAAAGAGTCATCCTGG CCAAATCATAACACTAACGGCGTGACTGCAGCTTGTTCCCACGAAGGGAAATCATCTTTC TACAGAAATCTGCTGTGGCTCACCGAAAAAGAGGGGAGTTATCCCAAGCTGAAAAACTCC TACGTTAATAAAAAGGGAAAAGAAGTGCTTGTCTTATGGGGTATCCATCACCCCCCAAAT TCTAAAGAACAGCAGAACCTGTACCAGAACGAGAACGCGTATGTGTCAGTGGTGACCTCT AACTATAATCGCAGATTTACACCAGAGATCGCAGAGCGCCCTAAAGTACGGGACCAGGCC GGTCGGATGAACTACTATTGGACCCTACTGAAACCAGGCGATACCATCATCTTCGAGGCT AATGGGAACTTAATTGCCCCCATGTACGCTTTCGCACTTAGCCGTGGCTTTGGCAGCGGG ATTATCACGTCTAATGCTTCCATGCACGAGTGTAATACGAAGTGTCAGACACCTCTTGGT GCCATTAACTCAAGTCTTCCCTATCAGAACATCCACCCGGTGACCATCGGCGAGTGTCCC AAGTACGTTCGAAGCGCCAAACTGCGGATGGTCACAGGTCTAAGGAATAACCCCTCCATC CAGAGCCGCGGCTTGTTTGGTGCGATTGCCGGGTTTATCGAGGGAGGGTGGACTGGCATG ATAGACGGATGGTACGGATACCACCACCAAAATGAACAAGGCTCCGGATACGCCGCCGAC CAAAAATCCACGCAGAACGCCATAAACGGAATTACAAACAAGGTAAACACAGTCATAGAA AAAATGAATATTCAGTTTACAGCCGTCGGGAAAGAATTTAACAAGCTGGAAAAGAGAATG GAAAACCTGAATAAGAAGGTCGACGATGGTTTTCTCGATATATGGACTTACAATGCTGAA CTTCTGGTCCTTCTGGAAAACGAACGAACCTTGGATTTCCATGACTCTAATGTGAAGAAC TTGTACGAAAAGGTGAAATCACAGTTAAAGAACAACGCCAAAGAAATAGGAAACGGGTGC TTCGAATTTTACCATAAATGTGATAACGAGTGTATGGAGAGCGTTCGTAATGGTACGTAC GACTATCCTAAATATAGTGAAGAGAGCAAACTCAACCGTGAAAAAGTAGACGGCGTGAAA CTGGAATCCATGGGGATCTACCAAATCCTGGCCATCTACTCGACGGTGGCAAGTTCTCTC GTGCTTCTTGTAAGCCTGGGTGCTATCTCTTTTTGGATGTGTAGTAACGGATCCCTGCAG TGTCGAATTTGCATT 478 ATGAAAGCAAATCTTTTAGTTCTTCTGTGTGCGTTGGCTGCAGCCGACGCAGACACTATC TGCATTGGCTACCATGCTAATAATAGCACTGACACTGTAGATACAGTGTTGGAAAAGAAC GTTACAGTGACTCACTCTGTCAATCTGCTGGAGGATTCCCATAACGGCAAATTGTGCCGT CTAAAGGGCATTGCGCCACTCCAGCTGGGAAAGTGCAATATCGCAGGCTGGCTCCTGGGC AACCCAGAATGCGACCCGCTGCTGCCTGTTCGCTCATGGTCATACATCGTCGAAACCCCT AACAGTGAGAACGGGATTTGCTATCCCGGGGATTTCATCGATTACGAAGAATTACGCGAG CAACTGAGTTCCGTGTCGTCTTTTGAGAGGTTTGAGATCTTCCCGAAGGAATCTTCATGG CCCAACCATAACACCAATGGTGTGACTGCTGCCTGTTCACACGAGGGCAAAAGCTCTTTC TACCGAAATCTACTGTGGCTCACAGAGAAAGAGGGATCGTACCCCAAGCTGAAAAATTCC TATGTGAACAAGAAAGGCAAAGAGGTGCTGGTGCTTTGGGGAATTCATCACCCACCCAAT TCTAAGGAGCAGCAGAATCTGTATCAGAACGAAAATGCCTATGTTTCCGTGGTAACATCT AATTATAATAGGCGATTCACACCTGAGATTGCAGAGCGGCCGAAAGTCCGAGACCAGGCA GGCCGCATGAACTATTACTGGACGCTTCTCAAACCAGGCGACACCATCATCTTCGAGGCC AATGGGAACTTGATCGCACCAATGTACGCGTTTGCCTTGAGTCGGGGCTTTGGGAGCGGT ATTATCACCTCGAACGCCTCTATGCATGAATGTAATACGAAGTGTCAGACCCCTCTGGGG GCAATAAATAGCTCACTGCCCTATCAGAACATCCACCCCGTGACCATCGGTGAGTGTCCC AAATACGTCAGGTCAGCTAAACTCCGTATGGTGACCGGCCTAAGGAATAATCCGTCCATT CAGTCCAGAGGTCTGTTCGGTGCAATCGCCGGGTTCATTGAGGGAGGATGGACGGGTATG ATCGACGGCTGGTATGGCTATCACCACCAGAACGAACAGGGTAGTGGCTACGCCGCTGAT CAAAAGTCCACTCAAAATGCTATCAACGGAATCACGAACAAAGTGAACACAGTGATAGAG AAGATGAACATTCAGTTCACCGCTGTGGGTAAAGAGTTTAATAAGCTGGAGAAAAGGATG GAAAATCTCAATAAGAAAGTTGACGATGGATTCCTTGACATTTGGACTTACAATGCCGAG CTGCTGGTGCTTCTGGAGAATGAGAGGACCTTAGACTTTCACGACAGCAACGTTAAAAAT CTCTATGAGAAAGTGAAATCACAGCTGAAGAATAATGCAAAAGAGATTGGGAATGGGTGC TTCGAGTTTTATCACAAATGCGATAACGAATGTATGGAGTCCGTGAGAAATGGAACGTAC GACTATCCTAAGTATAGCGAGGAAAGCAAACTCAACAGGGAAAAGGTGGACGGTGTTAAA CTCGAATCCATGGGGATTTATCAGATATTAGCGATCTATTCGACCGTGGCATCATCTCTC GTTCTTCTTGTGTCTTTGGGCGCCATCAGCTTTTGGATGTGTTCAAATGGCTCTCTGCAG TGTCGCATCTGTATT 479 ATGAAAGCCAATCTACTGGTCCTCCTCTGCGCCTTGGCTGCCGCAGATGCTGACACGATC TGTATTGGCTACCATGCGAACAATAGCACGGATACAGTGGACACCGTTCTGGAGAAAAAT GTCACCGTGACACATAGCGTAAACCTGCTCGAAGATTCCCACAACGGTAAGCTCTGTAGA CTCAAAGGTATTGCTCCCCTGCAGTTGGGCAAATGTAATATAGCCGGCTGGCTTCTCGGC AATCCCGAATGCGATCCCCTGTTGCCCGTGCGGTCTTGGTCTTATATCGTCGAAACCCCA AATTCAGAAAACGGAATTTGTTATCCTGGCGACTTCATCGATTACGAAGAGTTGAGGGAG CAGCTTTCAAGCGTTAGCAGTTTCGAGAGATTTGAGATATTTCCAAAGGAAAGTTCCTGG CCCAATCATAACACCAACGGCGTGACCGCCGCTTGCTCTCACGAAGGCAAAAGTAGTTTC TATCGAAATCTGCTCTGGCTGACGGAGAAGGAAGGAAGTTACCCCAAGCTGAAAAACTCC TACGTCAACAAGAAGGGCAAAGAAGTGCTCGTACTGTGGGGCATCCATCACCCTCCCAAT TCCAAAGAGCAGCAGAACCTGTATCAGAATGAGAACGCTTATGTATCCGTTGTGACTTCA AACTATAATCGCCGGTTCACTCCTGAGATCGCAGAGCGGCCCAAAGTGAGAGACCAGGCC GGGAGGATGAATTATTATTGGACACTCCTCAAGCCAGGCGACACAATTATTTTTGAGGCT AACGGGAACTTGATCGCTCCCATGTATGCGTTCGCCTTGTCAAGAGGATTCGGATCCGGG ATTATCACCTCTAATGCTTCGATGCACGAATGTAACACAAAGTGTCAAACTCCACTGGGA GCCATAAATTCGTCCTTGCCATATCAGAATATTCACCCTGTTACAATTGGCGAGTGTCCC AAGTATGTCCGCTCTGCCAAGTTACGGATGGTGACCGGGTTGCGCAACAACCCAAGTATA CAGTCACGCGGACTGTTCGGAGCTATCGCGGGATTCATTGAGGGAGGCTGGACAGGGATG ATCGATGGGTGGTACGGGTATCATCACCAGAACGAACAGGGATCGGGATATGCCGCGGAC CAAAAGTCAACACAAAACGCCATCAACGGTATTACCAATAAGGTCAACACAGTGATCGAA AAGATGAATATCCAGTTCACTGCTGTGGGCAAGGAGTTTAATAAACTGGAGAAGCGCATG GAGAACCTGAACAAGAAGGTTGACGACGGGTTCCTGGACATATGGACGTACAATGCCGAG CTGCTTGTCCTCCTGGAGAATGAGAGAACCCTGGATTTTCACGATTCTAATGTGAAGAAT CTGTATGAAAAAGTGAAGTCCCAACTCAAAAACAACGCAAAAGAGATCGGCAACGGATGC TTTGAATTCTATCATAAGTGCGATAATGAATGTATGGAAAGTGTGAGGAATGGGACTTAC GATTACCCGAAATATTCCGAAGAGAGCAAACTGAATCGCGAGAAAGTTGACGGTGTAAAG CTGGAGTCTATGGGAATTTACCAAATTCTGGCCATTTATTCTACCGTGGCATCAAGCCTG GTTCTGCTGGTGTCCCTTGGCGCCATTTCATTCTGGATGTGTTCCAATGGCAGCCTCCAG TGCCGGATATGTATC 480 ATGAAGGCTAACCTTTTGGTCCTTTTGTGCGCGCTTGCCGCGGCGGATGCAGACACCATT TGCATAGGATACCACGCCAATAATAGCACAGACACAGTGGATACAGTCCTTGAGAAAAAT GTCACTGTAACTCATAGTGTTAACTTGCTAGAAGACTCTCATAATGGTAAATTATGTCGG CTTAAGGGAATCGCGCCACTCCAATTGGGCAAATGCAACATTGCTGGCTGGTTGTTAGGT AATCCCGAGTGCGATCCCCTGCTCCCTGTCCGGTCTTGGTCTTACATCGTTGAAACACCC AACAGTGAGAATGGCATCTGTTACCCCGGAGACTTCATCGACTACGAAGAGCTGCGAGAG CAGCTTTCTTCCGTCTCCTCCTTTGAACGATTCGAAATCTTCCCCAAAGAGAGCTCATGG CCGAACCATAACACTAATGGAGTTACAGCCGCCTGCTCCCATGAGGGGAAAAGCAGTTTT TATAGGAACCTGCTGTGGCTGACAGAAAAGGAGGGCAGCTACCCCAAGCTGAAGAATTCT TACGTGAACAAGAAGGGCAAAGAAGTATTGGTGCTGTGGGGCATTCATCATCCTCCGAAC TCCAAGGAGCAGCAGAACCTTTACCAGAACGAGAACGCCTACGTATCAGTTGTTACTAGC AACTATAACAGACGATTCACTCCTGAAATCGCCGAGCGGCCTAAGGTTCGGGATCAGGCT GGGAGAATGAACTATTACTGGACCCTGTTGAAGCCTGGAGACACTATTATCTTTGAGGCA AATGGAAACCTGATCGCACCTATGTATGCTTTCGCACTCAGCCGGGGCTTTGGCTCCGGG ATCATCACTAGTAATGCTAGCATGCATGAGTGTAACACGAAATGTCAGACCCCACTGGGT GCTATAAACAGTTCCCTGCCTTATCAGAACATCCACCCTGTGACTATTGGAGAGTGTCCC AAGTACGTCAGGAGCGCAAAGCTCCGGATGGTCACAGGGCTGAGGAATAACCCAAGCATT CAGAGCCGGGGTCTATTTGGGGCCATCGCCGGATTCATCGAGGGAGGCTGGACTGGCATG ATCGATGGCTGGTATGGCTATCATCACCAAAATGAACAGGGATCCGGCTACGCCGCAGAC CAGAAATCTACACAGAATGCAATCAACGGAATCACAAATAAAGTGAATACCGTCATCGAG AAGATGAACATACAATTTACCGCTGTGGGTAAAGAGTTTAATAAACTAGAGAAACGGATG GAAAATCTTAATAAAAAGGTGGACGACGGGTTCCTCGATATTTGGACATATAATGCCGAG CTATTGGTGCTCCTGGAAAATGAAAGAACGCTTGATTTTCACGACTCTAACGTGAAAAAT CTGTACGAAAAGGTTAAGAGTCAGCTAAAGAACAATGCCAAAGAAATCGGAAATGGTTGC TTCGAGTTCTACCACAAATGTGATAATGAATGCATGGAATCAGTCCGAAACGGTACCTAC GATTATCCTAAATATTCTGAAGAATCAAAGCTAAACCGAGAGAAGGTCGATGGCGTCAAG CTTGAGAGCATGGGTATCTACCAGATACTGGCCATCTATAGTACTGTGGCATCTTCCCTG GTGCTTCTCGTGTCCCTGGGGGCGATCTCCTTTTGGATGTGTTCAAACGGATCCCTGCAG TGTCGGATATGCATC 481 ATGAAGGCCAACCTGCTGGTTCTGCTTTGCGCTCTCGCCGCCGCCGATGCTGATACTATT TGCATAGGTTATCATGCTAACAACTCCACTGATACTGTTGATACAGTTCTCGAAAAAAAC GTAACGGTCACTCACTCTGTAAACCTATTGGAAGACAGCCACAATGGGAAGTTGTGTAGG CTTAAAGGCATCGCTCCACTGCAGCTGGGCAAATGTAACATCGCAGGCTGGCTCCTGGGC AACCCGGAGTGTGATCCTTTACTGCCCGTCCGCTCCTGGTCTTACATTGTTGAGACACCC AACAGTGAAAACGGTATCTGTTATCCCGGCGATTTTATTGACTACGAGGAGTTGCGGGAA CAACTGTCTTCTGTGAGCAGTTTCGAGCGCTTCGAGATTTTTCCTAAGGAGTCTTCTTGG CCCAACCATAACACAAACGGGGTGACCGCTGCCTGCTCACACGAGGGCAAGAGTAGCTTC TATAGAAATCTTCTCTGGCTTACTGAAAAAGAGGGATCTTATCCAAAGTTGAAAAACAGT TATGTGAACAAGAAGGGAAAAGAAGTGCTGGTCCTTTGGGGGATCCATCACCCACCCAAC TCCAAGGAGCAGCAGAACCTGTACCAAAACGAGAACGCATATGTTAGCGTCGTGACCAGC AACTACAATCGCAGGTTCACTCCCGAGATCGCCGAGAGGCCTAAAGTTCGCGACCAGGCT GGACGGATGAACTACTATTGGACACTATTAAAGCCAGGCGATACCATAATATTTGAAGCA AATGGGAACTTAATTGCACCGATGTACGCCTTCGCACTGTCCCGGGGGTTCGGAAGCGGG ATTATTACCTCTAACGCCTCCATGCATGAGTGCAACACCAAGTGTCAAACACCCCTGGGA GCTATTAACTCTAGCTTGCCCTATCAGAACATCCACCCAGTCACTATCGGCGAGTGTCCT AAGTACGTTAGATCAGCCAAGCTGCGCATGGTTACGGGGCTTCGGAACAACCCCTCAATC CAATCTCGGGGGCTTTTCGGTGCAATCGCCGGCTTTATAGAAGGCGGTTGGACCGGAATG ATTGATGGCTGGTATGGCTACCACCACCAAAACGAACAGGGAAGCGGGTATGCTGCAGAC CAGAAGAGCACACAGAATGCTATCAATGGGATCACCAACAAAGTAAACACGGTGATTGAG AAAATGAATATTCAGTTCACAGCGGTGGGCAAGGAGTTCAACAAACTGGAGAAGCGTATG GAAAATCTGAATAAAAAAGTTGACGACGGTTTCCTAGACATCTGGACATATAACGCCGAG TTGTTGGTGCTCCTCGAAAACGAGCGCACACTCGACTTCCACGATTCTAACGTTAAGAAT CTTTACGAAAAAGTTAAATCGCAGCTGAAAAACAACGCGAAGGAGATCGGTAACGGCTGT TTCGAGTTTTATCATAAGTGTGATAATGAATGCATGGAATCCGTGCGGAACGGTACCTAC GATTATCCTAAATATTCAGAGGAGAGTAAACTCAATCGCGAGAAGGTCGATGGAGTCAAG CTTGAGAGTATGGGAATTTATCAGATTCTGGCAATCTATAGCACCGTCGCATCCAGTCTC GTCCTCCTTGTTTCACTGGGAGCTATTTCATTCTGGATGTGCTCTAACGGGTCGCTGCAG TGCAGAATCTGCATT 482 ATGAAGGCAAATCTTCTGGTACTTCTCTGCGCCCTCGCTGCAGCCGACGCAGATACCATT TGTATCGGCTACCACGCGAATAACTCAACGGATACCGTGGACACCGTGTTGGAGAAGAAC GTTACCGTCACACATAGTGTGAATCTGCTTGAAGATTCACATAACGGAAAACTTTGTAGG CTCAAAGGCATCGCGCCACTGCAGCTGGGGAAATGCAATATTGCAGGTTGGTTACTGGGT AACCCAGAATGCGATCCTCTGTTACCTGTGCGTAGTTGGAGCTATATCGTTGAGACCCCA AATTCGGAGAATGGGATCTGCTATCCAGGGGACTTCATTGACTATGAAGAGCTGCGAGAA CAGCTCAGCAGCGTATCTAGCTTCGAGAGATTTGAAATTTTCCCGAAGGAATCCAGCTGG CCAAACCACAATACCAATGGCGTTACGGCCGCCTGTAGCCACGAAGGTAAGTCTAGCTTC TACAGAAACCTGCTGTGGCTGACAGAAAAGGAGGGGTCTTACCCGAAGTTGAAGAATAGC TACGTCAATAAGAAAGGAAAAGAGGTCCTTGTCCTCTGGGGCATCCACCACCCTCCAAAC TCGAAGGAACAGCAGAACCTTTATCAGAACGAGAACGCTTATGTCTCCGTGGTGACATCC AATTATAACAGGCGTTTCACACCAGAGATAGCCGAAAGGCCCAAGGTCCGCGACCAAGCT GGTAGGATGAATTACTATTGGACACTCCTCAAACCAGGAGACACAATTATTTTTGAAGCA AATGGGAACCTGATTGCCCCCATGTATGCCTTTGCGCTAAGCCGCGGTTTCGGAAGCGGC ATTATCACGAGTAATGCATCAATGCACGAGTGTAACACCAAATGTCAAACCCCCTTGGGC GCAATTAACTCTTCCCTCCCTTACCAGAACATCCACCCCGTCACCATCGGTGAGTGCCCT AAATACGTACGGTCTGCTAAGTTGCGGATGGTCACCGGCCTGCGAAATAACCCTAGCATT CAGTCCAGAGGGTTATTTGGCGCGATCGCAGGATTCATCGAGGGAGGGTGGACCGGCATG ATAGACGGGTGGTATGGATACCATCATCAGAACGAGCAAGGCAGCGGCTACGCTGCTGAC CAAAAGAGCACGCAGAACGCGATCAATGGAATCACGAATAAGGTTAACACGGTCATCGAA AAGATGAACATACAGTTCACAGCTGTGGGCAAGGAGTTCAACAAGCTTGAAAAAAGAATG GAGAACTTGAACAAAAAAGTAGACGACGGCTTTCTCGATATTTGGACTTACAACGCCGAA TTGCTAGTCTTGTTGGAGAATGAACGCACCTTGGACTTCCACGACTCCAACGTCAAGAAT TTATACGAAAAGGTCAAAAGCCAGCTTAAGAATAACGCCAAGGAGATCGGCAATGGCTGT TTCGAATTTTACCATAAATGCGATAATGAATGTATGGAAAGTGTTAGGAACGGCACATAC GACTACCCTAAATACTCCGAAGAGAGCAAACTCAATCGGGAGAAGGTTGATGGAGTGAAG TTAGAGAGCATGGGAATTTACCAAATACTCGCCATCTATAGCACCGTTGCCTCAAGCCTG GTCCTCCTAGTGTCCCTGGGCGCCATTAGTTTCTGGATGTGTTCCAATGGGTCTTTGCAA TGTCGCATCTGTATA 483 ATGAAAGCTAACCTGCTGGTCCTCCTATGTGCTCTCGCTGCCGCAGATGCCGATACCATA TGCATTGGATATCACGCGAACAACAGCACCGATACGGTGGATACAGTGCTGGAAAAAAAC GTGACTGTGACACATTCTGTCAATCTCCTGGAAGACTCCCACAATGGCAAGCTGTGTCGT TTGAAGGGGATCGCCCCCCTGCAGCTCGGAAAGTGCAACATAGCAGGGTGGCTGCTCGGG AATCCAGAGTGCGATCCGCTGCTCCCGGTACGGAGCTGGTCTTACATTGTTGAGACACCT AACAGCGAGAATGGCATTTGTTATCCTGGAGACTTCATCGACTACGAGGAACTCCGGGAA CAGCTTAGCTCCGTAAGCAGCTTCGAAAGATTTGAGATTTTCCCTAAGGAGTCATCCTGG CCCAACCATAATACAAACGGAGTGACCGCTGCCTGTTCTCATGAAGGGAAAAGTTCCTTT TACAGAAATCTCCTGTGGCTGACTGAGAAAGAAGGAAGCTATCCTAAGCTGAAGAATTCT TACGTTAATAAGAAAGGAAAAGAAGTGCTGGTCCTCTGGGGGATACATCACCCCCCAAAT AGCAAGGAGCAACAGAATTTATATCAGAATGAGAACGCATACGTCTCGGTTGTGACTTCG AACTACAACAGGCGGTTTACACCCGAGATCGCAGAGCGCCCCAAGGTTAGAGACCAGGCT GGGAGGATGAATTACTATTGGACGCTTCTCAAGCCAGGGGATACCATTATTTTTGAGGCT AATGGCAATCTGATTGCCCCTATGTACGCCTTCGCTCTGTCAAGGGGATTTGGAAGCGGC ATCATCACCTCCAACGCTTCCATGCATGAGTGCAACACCAAGTGTCAGACACCCTTAGGC GCAATCAACAGCAGTCTGCCCTATCAAAACATTCATCCCGTGACAATCGGCGAGTGTCCG AAATACGTTCGATCCGCGAAGTTAAGGATGGTTACGGGCCTACGTAATAACCCTTCAATC CAGTCTCGTGGCCTCTTCGGTGCTATCGCTGGTTTCATCGAAGGAGGCTGGACAGGAATG ATCGACGGATGGTATGGATATCACCATCAGAATGAGCAGGGCAGTGGGTATGCCGCAGAC CAGAAATCCACCCAGAATGCCATAAATGGAATCACCAACAAGGTGAACACAGTTATCGAA AAGATGAACATCCAGTTCACCGCCGTGGGAAAGGAGTTTAACAAACTTGAGAAGAGAATG GAGAATCTTAATAAAAAGGTAGATGATGGGTTCCTTGATATCTGGACATATAACGCCGAG CTTCTAGTGCTCCTGGAGAACGAGAGGACTCTGGACTTTCACGACTCCAACGTCAAAAAC CTATACGAAAAGGTCAAGAGTCAACTGAAAAATAACGCAAAAGAGATAGGTAACGGATGT TTTGAGTTCTACCACAAATGCGATAACGAGTGCATGGAATCCGTGAGGAATGGTACCTAT GACTATCCAAAATATTCTGAGGAGTCCAAGCTCAACCGAGAAAAGGTGGACGGCGTAAAG CTCGAAAGCATGGGGATTTATCAGATACTTGCAATTTATTCCACTGTGGCTTCTTCCCTG GTGCTTTTGGTCAGCTTAGGGGCTATCAGCTTCTGGATGTGTTCCAACGGCTCCCTTCAG TGTAGAATTTGCATC 484 ATGAAGGCAAACTTGTTGGTGCTACTCTGCGCATTAGCAGCTGCTGACGCAGATACAATT TGTATCGGGTACCACGCCAATAACTCTACAGATACAGTAGATACCGTCCTTGAAAAAAAT GTCACCGTGACCCATAGTGTAAACCTCCTAGAAGATAGCCATAACGGCAAACTGTGTCGG CTTAAGGGCATCGCGCCTCTACAGCTGGGCAAGTGTAACATTGCTGGCTGGCTCCTTGGC AATCCTGAGTGCGACCCCTTGCTGCCAGTGAGGTCCTGGAGCTACATCGTGGAAACTCCC AATTCTGAGAATGGAATATGTTATCCGGGGGATTTCATCGACTACGAAGAGCTGCGCGAA CAACTCTCATCAGTCAGCTCCTTTGAAAGATTCGAAATCTTCCCCAAGGAATCTAGCTGG CCAAACCATAACACTAATGGAGTAACAGCTGCATGTTCCCACGAGGGCAAGAGCTCTTTT TACAGGAACCTCCTATGGCTGACGGAGAAAGAAGGGTCCTACCCCAAGCTGAAAAATAGC TACGTTAACAAGAAAGGAAAAGAGGTGTTGGTTCTGTGGGGAATTCATCATCCTCCCAAC AGTAAGGAGCAGCAGAATCTCTATCAAAATGAAAACGCTTACGTCAGTGTGGTGACGTCT AATTACAACAGGAGATTTACACCAGAGATTGCCGAGCGGCCGAAAGTGAGAGATCAGGCA GGCAGGATGAATTATTACTGGACACTTCTGAAACCTGGAGACACAATCATTTTCGAAGCT AATGGAAACCTCATCGCACCGATGTACGCATTCGCCTTGTCCCGGGGATTCGGCTCCGGC ATCATCACCTCCAACGCTTCAATGCATGAATGTAATACTAAATGCCAGACGCCGCTTGGC GCTATTAACTCATCCTTGCCTTATCAGAATATTCATCCCGTTACCATTGGAGAGTGTCCC AAATACGTGCGTTCAGCCAAACTGCGGATGGTCACTGGCCTGCGAAATAACCCTTCAATT CAATCTCGCGGACTGTTCGGAGCTATCGCCGGCTTCATAGAAGGGGGCTGGACCGGCATG ATTGACGGATGGTACGGTTACCATCACCAAAACGAGCAGGGTTCCGGCTATGCCGCCGAC CAGAAATCAACCCAGAACGCCATAAATGGTATTACCAACAAGGTTAATACGGTCATCGAG AAAATGAACATCCAGTTCACAGCAGTGGGAAAAGAATTTAATAAGCTCGAGAAAAGAATG GAAAACCTGAACAAAAAAGTGGACGATGGTTTCCTCGACATATGGACCTATAATGCTGAG CTACTCGTCCTTCTGGAAAATGAGCGAACGCTTGACTTCCACGATTCGAATGTGAAAAAC CTATACGAAAAAGTGAAGTCCCAGCTCAAGAACAATGCGAAGGAGATCGGGAACGGCTGC TTTGAGTTTTACCACAAATGTGATAACGAATGCATGGAGTCTGTGCGAAATGGGACATAC GACTATCCTAAGTATTCAGAAGAGTCAAAACTCAACCGGGAAAAGGTTGACGGAGTTAAG CTTGAGTCAATGGGAATTTACCAAATCCTGGCAATCTACTCTACTGTTGCCTCTTCACTC GTCCTCTTAGTTTCACTAGGGGCTATCAGTTTCTGGATGTGTTCTAATGGTAGCCTGCAG TGTCGAATTTGTATA 485 ATGAAAGCTAATCTCTTAGTTCTGCTCTGCGCCTTAGCGGCTGCAGATGCCGACACCATA TGCATTGGCTACCACGCTAATAACTCCACCGATACAGTGGACACCGTGCTGGAAAAGAAC GTCACTGTGACCCACTCAGTGAACCTGTTGGAGGATTCACACAACGGCAAGTTATGCAGA CTCAAGGGAATTGCACCACTGCAGCTGGGTAAGTGTAATATCGCTGGCTGGCTTCTCGGA AATCCCGAGTGCGACCCTCTGTTACCTGTCAGGAGCTGGAGTTATATCGTGGAAACTCCT AATAGTGAAAATGGAATATGCTATCCCGGCGACTTCATCGACTACGAGGAGCTAAGGGAA CAGCTGTCAAGCGTCTCCTCCTTCGAAAGATTCGAGATCTTCCCGAAGGAGAGTTCGTGG CCAAACCATAACACTAACGGGGTCACCGCGGCCTGTTCTCACGAGGGGAAGTCATCCTTC TACCGAAACCTTCTGTGGCTGACGGAGAAAGAAGGCAGCTATCCCAAACTGAAGAATAGT TACGTGAATAAGAAGGGAAAGGAGGTACTGGTCCTCTGGGGCATCCATCATCCCCCCAAC AGTAAGGAGCAGCAGAATCTTTACCAGAACGAGAACGCTTATGTGAGCGTCGTAACCTCA AACTACAACCGCAGGTTCACTCCTGAAATTGCCGAACGGCCGAAAGTGAGGGACCAAGCC GGCCGCATGAACTACTATTGGACGCTTCTCAAGCCCGGTGATACTATTATTTTCGAGGCA AACGGCAACTTAATCGCTCCTATGTACGCATTTGCACTGAGTCGGGGTTTTGGTTCGGGC ATCATCACCTCAAATGCTTCCATGCACGAATGCAATACAAAATGCCAGACCCCACTTGGA GCCATCAACTCCTCACTGCCTTATCAGAATATCCACCCAGTCACTATCGGGGAATGCCCG AAATATGTCAGAAGCGCTAAGCTTCGGATGGTGACCGGTCTGCGCAATAATCCGTCTATA CAATCCAGGGGACTGTTTGGCGCGATAGCCGGATTTATTGAGGGGGGATGGACTGGCATG ATCGATGGGTGGTACGGGTACCATCACCAGAATGAACAGGGTTCCGGCTACGCCGCAGAT CAAAAGTCCACCCAGAACGCTATTAACGGAATCACCAACAAGGTCAATACTGTCATTGAG AAAATGAATATCCAGTTCACTGCCGTGGGCAAGGAGTTCAATAAGCTAGAGAAGCGTATG GAAAACCTTAACAAGAAGGTGGACGATGGATTTTTGGATATTTGGACCTATAATGCTGAG TTGTTGGTCCTCCTGGAGAATGAAAGAACTCTGGACTTCCATGATAGCAATGTGAAAAAC CTCTACGAAAAAGTCAAATCACAGCTTAAGAACAACGCCAAAGAAATTGGGAATGGATGC TTTGAGTTTTACCATAAATGCGACAACGAGTGTATGGAGTCTGTCAGAAACGGCACATAC GATTACCCCAAGTATTCCGAAGAATCAAAACTGAATCGGGAAAAGGTTGATGGAGTGAAA TTAGAAAGCATGGGAATCTATCAAATTCTTGCAATTTATAGCACCGTTGCTAGCTCACTG GTCCTGCTCGTTAGTTTGGGCGCCATTAGCTTCTGGATGTGTAGCAATGGGTCTCTCCAA TGCAGAATTTGCATT 486 ATGAAAGCGAATCTGCTGGTCCTGCTGTGCGCCCTGGCGGCTGCTGACGCGGATACTATT TGCATCGGCTATCACGCTAATAACTCGACAGACACCGTGGATACAGTCTTGGAGAAAAAT GTGACTGTAACCCACTCGGTTAACCTTCTCGAGGACTCGCATAACGGGAAACTGTGTAGG CTGAAGGGAATCGCACCACTCCAGCTGGGCAAGTGCAATATAGCTGGCTGGCTGCTCGGG AATCCTGAGTGCGACCCTCTCCTGCCCGTCCGGTCCTGGAGCTATATAGTGGAAACACCT AACAGCGAGAATGGTATCTGCTATCCGGGGGATTTTATCGACTATGAGGAACTACGAGAA CAGCTCTCCTCCGTTAGCAGCTTCGAGCGATTTGAAATCTTTCCTAAGGAGAGCAGTTGG CCTAACCACAACACTAATGGGGTGACAGCCGCCTGTAGCCATGAGGGAAAGTCTTCTTTT TATAGAAACTTGCTGTGGTTGACTGAGAAAGAGGGGAGCTACCCGAAACTAAAGAACTCC TACGTGAACAAGAAAGGCAAAGAGGTTTTGGTTCTGTGGGGCATCCACCATCCTCCCAAT AGCAAGGAACAGCAGAATCTCTATCAGAACGAAAACGCCTACGTGTCAGTGGTGACCAGT AATTATAATCGACGCTTTACCCCCGAAATTGCAGAGCGGCCGAAAGTCCGCGACCAGGCC GGACGCATGAATTACTATTGGACCCTGCTAAAGCCCGGGGACACTATCATATTTGAAGCC AACGGGAACCTGATTGCACCCATGTATGCGTTTGCTCTGTCACGCGGGTTTGGTAGCGGG ATTATCACTTCCAACGCTTCAATGCATGAATGTAACACTAAGTGTCAGACCCCACTGGGC GCCATTAACAGCTCGCTGCCATACCAGAATATACACCCAGTTACTATTGGTGAATGTCCT AAGTATGTACGGTCCGCCAAGCTGCGGATGGTTACTGGCCTCAGGAACAATCCTTCAATT CAGTCTAGGGGGCTGTTCGGAGCCATAGCTGGCTTTATTGAGGGAGGCTGGACAGGCATG ATTGACGGCTGGTACGGCTACCACCATCAGAACGAGCAAGGCTCCGGCTACGCCGCGGAC CAGAAGTCAACTCAAAATGCGATAAACGGAATCACCAACAAGGTGAACACCGTCATAGAA AAAATGAATATACAATTCACAGCCGTGGGAAAGGAGTTCAATAAGCTCGAGAAGCGTATG GAGAATCTCAATAAAAAAGTGGATGATGGGTTCCTCGATATCTGGACCTATAACGCTGAA CTCTTAGTCCTCCTCGAAAACGAGCGAACGCTCGACTTCCATGATTCTAATGTAAAAAAT CTTTACGAAAAGGTTAAGTCACAGCTGAAGAACAACGCCAAGGAGATAGGAAACGGCTGT TTCGAGTTTTATCATAAGTGTGACAACGAGTGTATGGAATCTGTCCGCAATGGCACTTAT GATTACCCCAAGTACTCCGAGGAAAGTAAACTTAATAGAGAAAAAGTTGATGGCGTTAAG CTGGAGTCAATGGGGATTTATCAGATCCTAGCTATATATTCTACTGTGGCTTCTAGTCTC GTTTTGCTGGTGAGCCTGGGAGCCATAAGCTTTTGGATGTGTAGCAATGGGTCCCTCCAG TGTCGAATCTGTATC 487 ATGAAAGCCAACTTGCTGGTGTTGCTCTGCGCCCTTGCCGCCGCCGACGCAGATACCATT TGTATTGGCTACCATGCCAATAATTCTACGGACACTGTGGATACCGTCTTGGAGAAAAAT GTAACTGTAACTCACTCCGTTAATCTTCTCGAAGATTCACACAATGGCAAGCTGTGCCGC CTTAAAGGCATTGCCCCCTTGCAGCTGGGCAAGTGTAATATTGCTGGATGGCTCCTCGGC AATCCTGAGTGTGACCCCCTCCTGCCCGTTAGGTCGTGGAGCTACATTGTGGAGACCCCA AATTCGGAAAATGGGATATGTTACCCAGGCGACTTTATCGACTATGAGGAACTACGTGAG CAGCTGAGTTCTGTTTCCAGTTTTGAAAGATTTGAGATCTTTCCAAAGGAGAGCTCTTGG CCGAACCATAACACCAATGGGGTCACCGCCGCTTGCAGTCATGAAGGAAAATCAAGCTTC TACCGAAACTTGCTGTGGCTCACGGAAAAGGAGGGCTCCTACCCCAAGTTGAAGAACTCC TATGTGAACAAAAAGGGCAAAGAGGTTCTCGTGCTCTGGGGAATTCACCACCCTCCCAAC AGCAAGGAGCAGCAGAACTTGTATCAGAACGAAAATGCTTACGTTAGCGTGGTGACTTCC AATTATAATCGACGCTTTACACCGGAGATTGCTGAACGCCCGAAAGTTCGGGATCAAGCC GGCCGGATGAACTATTATTGGACCCTCCTGAAACCCGGTGATACTATTATTTTTGAGGCA AACGGAAACCTGATTGCTCCCATGTACGCCTTCGCCCTGTCCCGGGGGTTTGGCAGCGGA ATTATAACTAGCAACGCTAGCATGCACGAGTGTAATACTAAGTGTCAGACCCCTCTGGGG GCAATAAACTCCAGCTTACCTTATCAGAACATCCACCCTGTTACCATAGGCGAGTGCCCG AAGTACGTTAGGTCAGCTAAGCTAAGAATGGTCACTGGTTTGAGGAATAACCCCAGCATT CAGAGTAGGGGGCTGTTTGGGGCAATTGCAGGTTTTATCGAGGGCGGTTGGACTGGTATG ATCGACGGCTGGTATGGATATCATCATCAGAATGAGCAGGGGTCTGGGTATGCTGCGGAC CAGAAGTCCACGCAAAATGCCATAAACGGAATCACGAATAAGGTTAATACCGTCATCGAA AAAATGAACATTCAGTTTACTGCGGTGGGTAAGGAATTCAATAAACTCGAAAAGAGAATG GAGAACTTAAATAAGAAAGTCGACGACGGATTTTTGGATATCTGGACCTATAACGCCGAA CTCCTCGTTCTGTTGGAGAACGAGCGCACCCTCGACTTCCACGATAGTAACGTGAAAAAT CTGTATGAGAAGGTGAAGTCCCAGCTCAAGAACAATGCCAAGGAAATCGGAAACGGATGT TTTGAGTTCTACCACAAGTGCGACAATGAATGCATGGAGAGTGTGCGCAATGGGACGTAC GACTACCCTAAATATAGTGAAGAGTCTAAGCTCAACCGGGAGAAGGTGGACGGAGTGAAG CTGGAGAGTATGGGAATTTACCAGATACTGGCTATCTACAGTACAGTTGCCAGCTCCCTC GTTCTTCTGGTGTCTCTGGGGGCCATCTCTTTCTGGATGTGTTCCAATGGCAGCCTCCAA TGCCGGATCTGCATT 488 ATGAAAGCAAATCTTCTGGTGTTACTATGCGCATTAGCTGCCGCTGACGCCGACACCATT TGCATTGGCTATCACGCCAATAATAGCACTGACACTGTCGACACAGTTCTTGAAAAGAAC GTGACTGTTACCCACTCCGTGAATCTACTCGAGGATTCTCATAACGGAAAGCTCTGTCGC CTTAAGGGTATTGCCCCTCTCCAGCTTGGAAAATGCAACATTGCTGGCTGGCTGCTTGGA AACCCTGAATGTGACCCACTCCTGCCCGTCCGGAGCTGGAGTTACATAGTGGAGACTCCA AATAGCGAGAACGGTATATGTTACCCAGGTGATTTCATTGACTATGAGGAGTTGAGAGAG CAGTTGAGCTCCGTTTCGTCTTTTGAAAGGTTCGAGATCTTCCCAAAAGAGTCAAGCTGG CCTAACCATAACACCAATGGTGTTACGGCCGCATGTAGCCATGAGGGCAAGTCGTCCTTT TATCGAAATCTCCTATGGCTCACAGAGAAGGAAGGATCTTACCCAAAGCTCAAGAACTCG TACGTAAACAAGAAGGGGAAGGAAGTCCTTGTTCTGTGGGGTATACATCACCCACCAAAT TCCAAGGAACAGCAGAATTTATATCAGAACGAAAACGCATATGTTTCTGTCGTTACATCC AACTATAACCGGAGATTCACCCCAGAGATCGCCGAAAGACCGAAGGTGCGGGACCAGGCA GGGCGAATGAACTATTACTGGACATTGCTCAAGCCCGGAGACACCATAATTTTCGAGGCT AATGGCAACCTCATTGCCCCGATGTACGCATTCGCTCTTTCTCGGGGATTTGGCAGTGGG ATTATCACCTCGAACGCCTCCATGCATGAATGTAATACTAAATGTCAAACACCACTGGGA GCCATTAACAGTAGCCTGCCCTATCAAAATATCCACCCGGTCACTATTGGGGAGTGCCCA AAGTATGTGCGGTCTGCAAAGTTGAGAATGGTTACCGGGCTGCGCAACAATCCAAGTATT CAGAGTAGGGGGCTATTTGGTGCAATAGCAGGCTTTATCGAAGGGGGCTGGACTGGAATG ATAGATGGCTGGTATGGATATCACCACCAGAACGAGCAGGGTAGCGGCTACGCCGCCGAT CAGAAGAGCACTCAGAATGCTATCAACGGAATCACAAATAAAGTTAATACCGTAATAGAA AAGATGAATATCCAGTTCACAGCTGTGGGTAAAGAGTTCAACAAGCTGGAAAAACGGATG GAAAACCTGAATAAAAAGGTGGATGATGGTTTCCTCGATATATGGACTTATAACGCTGAG CTTCTGGTTCTGCTGGAAAATGAACGCACACTGGACTTCCACGATAGTAATGTAAAAAAT CTGTATGAAAAGGTTAAATCACAACTGAAAAATAATGCTAAGGAAATTGGGAACGGGTGT TTCGAATTCTATCACAAGTGCGATAATGAGTGTATGGAGTCAGTTCGGAACGGGACCTAC GATTATCCTAAGTATTCAGAAGAGTCTAAACTGAACCGCGAAAAAGTGGATGGAGTCAAA CTGGAGTCGATGGGCATCTATCAGATCCTCGCCATTTATAGCACCGTGGCATCGTCCCTG GTGCTTTTGGTTAGCCTGGGCGCCATTAGTTTCTGGATGTGTAGTAACGGGTCTCTGCAG TGTAGGATTTGTATT 489 ATGAAGGCAAATCTGCTCGTGTTACTCTGCGCTTTGGCCGCCGCTGACGCCGACACTATT TGCATCGGTTACCACGCCAACAACAGCACCGATACAGTGGACACGGTATTGGAAAAAAAC GTAACTGTGACACATTCAGTAAACCTGCTCGAGGACAGCCACAACGGTAAGCTGTGCCGG TTGAAAGGTATCGCACCACTGCAGCTTGGAAAATGTAATATCGCCGGGTGGCTGCTGGGC AATCCTGAGTGTGATCCTCTGCTCCCTGTACGGAGTTGGTCGTATATTGTGGAAACCCCT AACAGCGAAAACGGGATTTGTTATCCTGGCGACTTTATCGACTATGAGGAGCTCCGGGAG CAGCTGTCCAGCGTAAGTTCATTCGAGAGGTTCGAGATTTTCCCCAAAGAGAGTTCCTGG CCTAACCACAACACAAACGGTGTGACAGCTGCCTGCAGCCACGAGGGGAAGTCCTCATTC TATAGGAATTTGCTCTGGCTGACCGAAAAGGAAGGTTCGTACCCGAAGCTTAAAAATTCT TACGTTAACAAAAAGGGGAAGGAGGTACTCGTTCTGTGGGGGATCCATCATCCCCCAAAT TCTAAGGAACAGCAGAACCTATACCAGAATGAAAACGCATATGTCAGCGTGGTCACATCT AACTACAACAGACGCTTCACACCCGAAATCGCTGAGCGCCCCAAGGTACGAGATCAGGCT GGCAGGATGAACTACTATTGGACTTTACTGAAGCCGGGCGATACAATAATTTTCGAGGCT AACGGAAATCTGATCGCCCCAATGTATGCCTTTGCTCTTTCCCGCGGCTTTGGTTCAGGG ATTATTACTTCTAACGCTTCGATGCACGAGTGTAATACCAAATGCCAGACCCCGCTGGGC GCCATTAATAGCTCATTGCCTTATCAGAATATCCATCCCGTTACCATTGGCGAATGTCCC AAGTATGTGAGGAGCGCAAAACTTCGGATGGTAACAGGTCTAAGGAATAACCCTAGCATT CAGTCACGGGGGCTGTTTGGGGCAATAGCAGGCTTTATTGAGGGCGGATGGACAGGCATG ATCGATGGCTGGTATGGTTACCACCATCAGAACGAGCAGGGCTCTGGATATGCAGCCGAC CAGAAGAGTACACAAAATGCAATCAATGGCATTACTAACAAAGTGAACACGGTCATTGAA AAAATGAATATCCAGTTCACAGCCGTGGGAAAGGAGTTTAACAAGCTGGAAAAACGGATG GAAAATCTAAATAAGAAAGTCGACGACGGTTTTTTGGATATCTGGACCTACAACGCTGAA CTACTGGTTCTTCTGGAGAACGAAAGAACCCTGGACTTTCACGACTCTAATGTGAAGAAT CTGTACGAAAAAGTGAAGTCTCAGTTGAAGAACAACGCTAAAGAGATTGGGAATGGCTGT TTCGAATTCTACCACAAATGCGATAATGAGTGCATGGAGTCTGTCAGGAATGGTACTTAC GACTATCCCAAGTATTCTGAGGAGAGTAAGCTCAACAGGGAAAAAGTCGACGGAGTCAAA CTGGAGTCGATGGGCATATACCAGATTCTAGCCATCTACTCCACCGTGGCCAGTAGTTTA GTCTTGCTCGTAAGCCTTGGCGCTATCTCCTTCTGGATGTGCTCCAATGGATCCCTGCAG TGTAGAATCTGTATC 490 ATGAAGGCGAATCTACTGGTTTTATTGTGCGCCCTCGCTGCTGCCGACGCCGATACCATC TGCATCGGATACCATGCCAATAACTCCACAGATACCGTGGACACTGTGCTGGAAAAGAAT GTTACAGTGACACATTCAGTGAACCTGCTGGAAGATAGTCATAATGGCAAACTGTGTAGA CTAAAGGGCATCGCCCCCCTGCAACTTGGTAAGTGTAACATCGCTGGTTGGCTTCTGGGG AACCCCGAATGCGATCCACTGCTGCCTGTCCGCAGTTGGTCCTATATTGTCGAAACCCCC AACTCTGAAAACGGGATTTGTTATCCAGGAGACTTCATTGACTATGAAGAATTGCGGGAA CAGCTTTCAAGTGTGAGCTCTTTCGAACGGTTTGAAATCTTTCCGAAGGAGTCCTCGTGG CCAAATCATAACACTAATGGCGTGACAGCGGCATGTAGTCACGAAGGAAAATCTTCCTTT TATAGAAACCTCCTGTGGCTGACAGAGAAGGAAGGCAGTTATCCCAAACTGAAGAACAGT TACGTCAATAAAAAGGGGAAAGAAGTACTGGTACTTTGGGGAATCCACCATCCCCCCAAC AGCAAGGAGCAGCAGAATCTTTATCAAAATGAGAACGCCTACGTCAGCGTGGTGACCTCG AATTACAACAGGCGGTTCACACCAGAAATCGCGGAAAGGCCGAAGGTGCGGGATCAGGCC GGCAGGATGAACTACTATTGGACTCTCCTAAAACCAGGCGACACTATTATATTTGAAGCC AACGGCAACCTTATCGCTCCAATGTACGCCTTCGCTTTGAGCCGTGGGTTTGGCTCCGGA ATTATAACATCAAATGCAAGTATGCACGAGTGCAACACAAAGTGCCAGACACCACTCGGA GCAATCAACAGCTCCTTGCCATACCAAAACATTCATCCTGTTACCATCGGCGAATGCCCG AAGTATGTGAGGAGCGCAAAACTGAGGATGGTGACGGGCTTGCGGAACAACCCTTCTATC CAGTCCCGGGGCCTGTTTGGAGCGATCGCAGGATTCATTGAAGGGGGATGGACGGGGATG ATCGATGGATGGTACGGATATCATCACCAAAATGAACAAGGGTCAGGTTATGCTGCTGAT CAAAAGTCAACACAGAATGCAATCAACGGCATAACCAATAAAGTTAACACAGTGATTGAA AAAATGAATATTCAGTTTACCGCCGTGGGAAAAGAGTTCAATAAACTGGAGAAGAGGATG GAGAATTTGAACAAGAAGGTAGATGACGGCTTTCTCGACATTTGGACTTATAATGCAGAG CTATTAGTGCTCCTCGAGAATGAGAGAACTCTTGACTTTCACGACAGTAACGTAAAAAAC CTCTATGAAAAGGTCAAATCACAGCTTAAGAATAATGCAAAAGAGATCGGAAACGGATGC TTCGAATTTTACCACAAATGCGACAACGAATGTATGGAATCCGTGAGGAACGGTACCTAC GATTACCCCAAGTACAGCGAGGAAAGCAAGCTGAATCGAGAAAAAGTTGACGGTGTGAAG CTGGAGTCCATGGGCATCTACCAGATTCTTGCTATCTATTCTACAGTAGCTTCCTCCCTT GTACTTCTGGTGTCCCTGGGTGCCATTTCATTCTGGATGTGCAGCAACGGTTCCTTGCAG TGTCGGATCTGCATA 491 ATGAAAGCTAATCTTCTCGTGTTGCTGTGCGCCTTAGCGGCCGCAGACGCGGACACAATC TGTATTGGGTACCATGCCAATAATTCCACTGACACCGTAGACACTGTACTGGAAAAGAAT GTGACGGTAACCCACTCCGTTAATCTGCTGGAGGACTCTCACAACGGCAAACTCTGTCGG CTGAAAGGTATTGCACCACTTCAGCTGGGGAAGTGTAACATTGCCGGATGGCTACTAGGC AACCCTGAATGTGACCCCCTGCTGCCAGTGCGAAGCTGGAGTTACATTGTGGAAACTCCC AATAGTGAAAACGGTATCTGCTACCCTGGCGATTTCATTGATTATGAAGAGCTGAGGGAA CAGCTTTCTAGTGTGTCGTCCTTCGAGAGGTTTGAGATCTTCCCCAAGGAGAGCTCATGG CCAAACCACAATACAAACGGGGTCACTGCGGCATGTAGCCATGAGGGCAAGTCATCCTTC TATCGAAACCTCCTGTGGCTGACCGAAAAGGAAGGTAGCTACCCCAAACTTAAAAACAGT TATGTGAACAAAAAGGGCAAGGAAGTCTTAGTGCTTTGGGGCATCCACCACCCCCCAAAT AGCAAAGAGCAACAGAATTTGTACCAGAACGAAAATGCTTATGTGTCTGTAGTAACCTCT AACTATAACAGGCGTTTCACTCCCGAGATTGCCGAGCGACCGAAAGTTAGAGACCAGGCC GGACGCATGAATTACTACTGGACCCTGTTGAAACCTGGAGATACGATAATCTTTGAGGCC AACGGAAACCTGATAGCTCCTATGTATGCGTTCGCACTCAGTCGCGGGTTCGGGTCCGGG ATAATCACCAGTAACGCGTCCATGCACGAGTGTAATACGAAGTGCCAGACCCCACTAGGA GCGATTAACTCGTCTCTGCCATATCAGAATATCCATCCTGTGACAATCGGAGAGTGTCCT AAATACGTCCGCTCAGCCAAACTGCGAATGGTGACGGGCCTTCGCAACAATCCCAGTATC CAGTCTCGGGGACTCTTTGGAGCCATCGCCGGTTTTATCGAAGGCGGATGGACTGGGATG ATCGATGGCTGGTACGGCTACCACCACCAAAATGAGCAAGGCTCCGGGTACGCTGCCGAC CAGAAGTCAACTCAGAATGCAATTAACGGGATCACCAACAAGGTTAACACCGTAATCGAA AAGATGAACATCCAGTTCACGGCCGTGGGGAAGGAGTTTAATAAACTTGAGAAACGGATG GAGAACCTCAACAAAAAGGTGGACGACGGCTTTCTGGACATCTGGACCTATAATGCTGAG CTTTTGGTGCTGCTGGAAAACGAGCGCACACTGGATTTCCACGATAGTAATGTGAAGAAC CTGTACGAAAAGGTTAAGTCCCAACTCAAAAATAACGCGAAAGAAATCGGCAATGGGTGC TTTGAATTTTATCACAAGTGTGACAACGAATGCATGGAATCTGTGCGGAATGGGACCTAC GATTACCCAAAATATAGCGAAGAATCCAAGCTGAACAGAGAGAAGGTGGACGGCGTGAAA CTCGAAAGTATGGGTATCTACCAAATCCTAGCCATCTACTCTACCGTTGCCAGTAGTCTA GTGTTGCTGGTGTCGTTAGGTGCCATCTCTTTTTGGATGTGTAGCAATGGCTCTCTGCAA TGTCGGATCTGTATC 492 ATGAAGGCCAACCTGCTTGTGCTGCTTTGCGCACTAGCCGCTGCAGACGCCGACACAATT TGTATTGGATACCATGCTAATAACTCGACCGACACAGTTGACACAGTCCTTGAGAAGAAC GTGACAGTTACTCACTCCGTGAACCTGCTCGAGGACTCGCATAATGGCAAACTCTGCCGT CTGAAGGGTATCGCCCCCCTCCAACTGGGGAAATGCAATATAGCCGGCTGGCTGCTGGGA AATCCAGAGTGCGATCCACTGTTGCCTGTGCGCAGTTGGAGTTATATCGTGGAGACACCC AACTCAGAGAACGGTATCTGCTACCCTGGGGACTTCATAGATTATGAAGAGCTGCGCGAG CAGCTATCTTCCGTTAGCTCTTTCGAACGCTTTGAAATCTTTCCTAAAGAAAGCAGCTGG CCAAATCATAACACAAACGGAGTGACAGCTGCCTGCAGTCACGAGGGTAAAAGTTCTTTT TATAGAAATCTCCTGTGGTTGACGGAGAAAGAGGGCAGCTATCCAAAGCTCAAGAATAGC TACGTCAATAAAAAAGGTAAGGAGGTGCTAGTCTTATGGGGAATCCATCACCCACCCAAT TCCAAGGAACAGCAGAACCTCTATCAGAACGAGAACGCCTATGTGTCCGTAGTGACTAGC AACTATAATCGTAGATTCACACCTGAGATTGCAGAGAGACCCAAGGTTAGAGACCAAGCC GGCCGCATGAATTATTACTGGACACTGCTTAAACCCGGGGATACTATCATCTTCGAAGCG AATGGAAACCTGATCGCTCCAATGTATGCTTTTGCTCTGTCCAGGGGTTTTGGCTCGGGG ATTATCACAAGCAACGCATCTATGCACGAGTGTAATACCAAGTGTCAGACCCCCCTTGGC GCTATCAACTCTAGTCTACCGTACCAGAACATCCACCCTGTTACCATTGGTGAATGCCCG AAATACGTGCGGAGTGCCAAGCTGAGAATGGTGACCGGCCTGAGGAACAATCCTTCCATC CAGTCCCGGGGACTTTTCGGAGCTATCGCTGGCTTCATTGAAGGTGGGTGGACCGGCATG ATCGACGGGTGGTATGGATATCACCATCAGAACGAGCAAGGAAGCGGGTATGCTGCAGAC CAGAAGTCCACACAGAACGCAATAAACGGCATCACTAACAAAGTGAACACCGTGATTGAA AAAATGAATATACAGTTTACCGCCGTAGGGAAGGAATTTAATAAACTGGAAAAGCGCATG GAAAATTTGAACAAAAAAGTCGACGATGGTTTTTTAGACATTTGGACCTATAATGCGGAA CTGCTAGTACTGCTCGAGAACGAACGGACCCTCGACTTTCACGATTCAAACGTCAAAAAT CTATACGAGAAGGTGAAGTCGCAGCTGAAGAATAATGCCAAAGAAATCGGCAACGGATGT TTCGAATTCTACCACAAATGCGACAATGAATGTATGGAATCTGTTAGAAACGGCACGTAT GATTACCCCAAGTACAGCGAAGAATCTAAACTCAACCGGGAGAAAGTCGACGGAGTTAAG CTTGAGTCCATGGGAATCTATCAGATCTTGGCGATCTATTCCACCGTGGCAAGTTCCCTC GTATTGCTGGTGTCCCTTGGAGCAATTTCATTCTGGATGTGCAGTAACGGCAGCCTTCAA TGCCGCATCTGTATA 493 ATGAAGGCAAACCTTCTTGTCCTGCTGTGCGCACTCGCCGCAGCCGACGCCGACACAATC TGCATTGGGTATCACGCTAATAATTCAACTGACACTGTGGATACCGTACTGGAAAAGAAT GTTACTGTGACTCATAGTGTAAATCTGCTCGAGGACAGTCACAATGGAAAACTTTGCCGG TTAAAGGGCATCGCACCCCTGCAGCTGGGTAAGTGCAACATCGCGGGATGGCTGCTGGGC AACCCCGAGTGTGATCCCCTGCTTCCAGTGCGGTCTTGGTCTTACATTGTCGAAACACCC AACTCTGAAAACGGAATTTGTTACCCTGGCGACTTCATCGACTACGAAGAGCTTAGAGAG CAGCTATCGAGCGTGAGTTCTTTTGAAAGATTTGAGATCTTCCCAAAGGAAAGCTCTTGG CCCAACCATAATACTAATGGCGTCACAGCCGCCTGCTCACATGAAGGGAAGTCTTCTTTC TACAGGAATCTGTTGTGGTTGACGGAGAAGGAGGGAAGTTATCCAAAGCTTAAAAATTCC TACGTGAACAAGAAGGGTAAAGAGGTCCTGGTGCTCTGGGGCATCCACCATCCTCCGAAC TCCAAAGAACAGCAGAATCTGTATCAGAACGAAAATGCATATGTCAGTGTGGTGACAAGT AATTATAACCGCCGCTTTACCCCCGAGATCGCCGAACGCCCGAAGGTACGGGACCAAGCG GGTCGGATGAACTACTATTGGACCCTGCTAAAGCCTGGGGACACTATCATCTTCGAGGCC AACGGTAACCTGATCGCTCCCATGTATGCGTTTGCCCTGAGCAGAGGATTCGGCTCTGGA ATCATAACGAGCAACGCCTCAATGCATGAATGCAACACTAAGTGTCAAACTCCCTTGGGC GCAATAAACTCATCCTTGCCATATCAGAACATCCACCCAGTCACCATCGGGGAGTGCCCT AAATATGTGCGTTCAGCCAAGTTACGCATGGTAACGGGACTCCGGAATAACCCCAGCATT CAATCTCGAGGGCTTTTTGGAGCTATCGCAGGATTCATTGAAGGGGGCTGGACTGGGATG ATCGATGGATGGTATGGGTACCATCATCAGAACGAGCAGGGCTCCGGCTACGCAGCCGAT CAGAAGAGCACTCAGAACGCCATCAATGGCATCACAAACAAAGTCAACACTGTGATTGAA AAAATGAATATACAGTTTACCGCAGTGGGTAAGGAATTCAACAAGCTGGAGAAACGGATG GAAAATCTAAACAAGAAAGTGGATGATGGCTTTCTCGACATCTGGACCTACAACGCCGAA CTGCTGGTCCTGCTGGAAAATGAGCGCACACTGGATTTCCACGACTCGAACGTCAAGAAT CTATACGAGAAAGTGAAATCCCAGCTCAAGAATAATGCCAAGGAGATCGGCAACGGATGC TTCGAATTTTACCATAAATGCGACAACGAGTGTATGGAGTCCGTCCGAAACGGGACATAC GACTATCCCAAGTATTCAGAAGAGTCAAAGCTTAACCGCGAAAAGGTGGATGGCGTTAAG CTGGAATCTATGGGTATTTACCAGATACTGGCCATTTATAGCACTGTGGCTAGCTCATTA GTGCTGCTGGTGTCGCTGGGAGCGATTTCCTTTTGGATGTGTAGCAACGGGAGTTTACAG TGCCGGATTTGCATC 494 ATGAAGGCTAACCTCCTGGTGCTGCTGTGTGCCCTGGCTGCAGCGGACGCCGACACGATC TGTATCGGATACCATGCTAATAATTCTACCGACACTGTAGACACCGTGCTGGAAAAGAAT GTTACAGTGACCCATAGTGTTAATCTCCTCGAAGATTCACACAACGGCAAGCTCTGCCGT CTCAAAGGAATAGCACCTCTTCAGCTGGGCAAGTGTAACATCGCCGGGTGGCTTCTGGGC AACCCCGAATGTGATCCCCTTCTGCCAGTCCGCTCATGGTCCTATATTGTGGAAACCCCT AATTCCGAGAACGGAATTTGTTATCCCGGAGACTTTATTGATTATGAGGAACTTAGAGAA CAACTGTCTTCGGTCTCGTCCTTTGAGAGGTTCGAGATTTTCCCTAAGGAGAGCTCCTGG CCCAATCACAACACTAACGGTGTGACCGCCGCCTGCTCGCATGAGGGGAAGTCCTCTTTC TACCGCAACCTCCTGTGGCTGACAGAGAAGGAGGGGTCCTATCCCAAACTAAAAAACTCA TACGTGAACAAAAAGGGAAAAGAGGTCTTGGTTCTCTGGGGCATCCATCACCCACCAAAC AGTAAGGAGCAGCAAAATCTGTACCAGAATGAAAACGCATATGTTAGCGTAGTGACCTCT AACTATAACAGGCGGTTTACTCCAGAGATTGCCGAGCGGCCCAAAGTGCGAGACCAGGCA GGAAGGATGAACTATTATTGGACTTTGTTAAAACCCGGAGACACAATTATCTTCGAGGCA AACGGGAACTTGATCGCACCCATGTACGCCTTCGCACTGAGCAGGGGTTTCGGCTCCGGC ATCATCACTTCTAATGCCTCTATGCACGAGTGTAATACGAAGTGTCAGACCCCATTGGGA GCCATCAACTCCAGTCTGCCCTATCAGAACATCCATCCGGTGACTATAGGCGAATGCCCC AAGTACGTCAGGTCCGCTAAGCTCCGCATGGTCACCGGACTTAGGAACAACCCGAGTATT CAGAGCCGAGGCCTGTTCGGAGCCATCGCAGGGTTCATAGAGGGAGGGTGGACCGGGATG ATAGATGGATGGTATGGCTACCATCATCAAAACGAACAGGGCAGCGGATATGCAGCTGAT CAGAAGTCCACCCAGAACGCCATAAACGGAATCACCAACAAAGTGAACACCGTCATAGAA AAAATGAACATACAGTTCACCGCCGTGGGCAAAGAATTCAATAAACTTGAAAAACGGATG GAAAATTTGAATAAGAAGGTGGATGACGGCTTCCTGGATATCTGGACTTACAATGCGGAG CTGCTCGTGCTTCTGGAGAACGAGAGAACGCTCGACTTCCACGATTCTAACGTTAAGAAC CTGTATGAGAAAGTTAAAAGTCAGCTCAAAAATAACGCGAAGGAAATCGGGAACGGCTGC TTTGAATTTTACCATAAATGCGATAATGAGTGCATGGAATCCGTGCGAAACGGCACGTAC GACTATCCAAAGTATTCAGAGGAATCAAAATTGAACAGAGAAAAGGTCGATGGTGTGAAA CTGGAGAGTATGGGGATATATCAAATCCTTGCGATCTACTCTACTGTGGCTTCTTCCCTG GTCCTGCTGGTGTCCTTGGGGGCAATTTCATTTTGGATGTGTTCTAATGGGAGTTTACAG TGCAGGATCTGCATA 495 ATGAAAGCCAATCTTCTGGTTCTGCTCTGCGCTCTAGCTGCTGCCGATGCTGACACTATT TGTATAGGCTACCACGCAAATAATTCGACGGATACTGTCGACACGGTCCTGGAAAAAAAT GTCACAGTGACTCATTCAGTTAATCTCTTGGAGGATTCTCACAATGGAAAGTTGTGTAGA CTGAAGGGCATTGCTCCATTGCAGCTTGGGAAGTGTAATATCGCGGGCTGGTTACTGGGC AACCCTGAATGCGACCCCCTCTTGCCTGTCCGGTCCTGGTCTTATATCGTGGAGACACCA AATTCTGAGAATGGAATCTGCTATCCGGGTGACTTTATCGATTACGAGGAGCTTCGGGAG CAGCTGTCTTCAGTGTCCAGTTTTGAAAGATTTGAGATATTTCCTAAGGAGAGCTCCTGG CCAAATCATAATACCAATGGCGTGACAGCCGCATGTTCACACGAAGGAAAAAGCTCCTTC TATCGGAACCTGCTCTGGCTTACAGAAAAGGAAGGCTCTTACCCCAAACTCAAGAACAGT TACGTGAATAAGAAAGGTAAAGAGGTTCTAGTACTCTGGGGCATCCACCACCCGCCAAAC AGCAAGGAGCAACAGAACCTCTATCAGAACGAGAATGCCTACGTGTCCGTGGTCACATCA AACTATAACCGCAGGTTTACACCAGAAATTGCAGAGCGGCCTAAAGTCCGTGATCAGGCA GGCAGGATGAACTATTACTGGACTTTGCTGAAGCCGGGAGACACCATTATCTTCGAGGCG AATGGGAACCTCATTGCCCCAATGTACGCCTTCGCGCTCTCTCGCGGCTTTGGCTCAGGA ATTATCACGTCAAATGCTTCTATGCACGAGTGTAATACAAAATGTCAGACCCCTCTGGGC GCCATAAACTCTTCCCTGCCTTATCAAAATATTCACCCAGTGACTATTGGGGAGTGCCCC AAATACGTTAGAAGCGCTAAACTGCGTATGGTAACGGGTTTGCGGAACAACCCAAGTATC CAGAGCCGCGGCCTGTTTGGCGCCATTGCTGGTTTTATTGAGGGGGGTTGGACAGGAATG ATCGATGGATGGTACGGCTACCACCATCAGAATGAACAGGGGAGTGGGTACGCCGCCGAC CAAAAGTCCACACAGAATGCGATCAACGGGATCACTAACAAGGTGAACACCGTGATTGAG AAGATGAACATACAGTTTACCGCAGTCGGAAAGGAATTCAACAAACTTGAAAAACGCATG GAGAATCTGAATAAAAAAGTGGACGACGGATTTTTAGATATATGGACCTATAATGCCGAA TTGCTGGTGCTCTTAGAAAACGAACGAACGCTGGACTTCCACGATTCTAACGTTAAAAAC CTTTATGAGAAGGTTAAGAGCCAGTTGAAGAACAACGCGAAGGAAATCGGAAACGGATGC TTCGAATTTTACCACAAGTGTGACAACGAGTGTATGGAATCTGTTAGAAATGGCACCTAC GATTATCCAAAGTACTCAGAAGAAAGCAAACTTAACAGGGAAAAGGTGGATGGTGTGAAA CTGGAGTCCATGGGTATCTACCAGATACTTGCAATCTACTCTACGGTTGCTTCAAGCTTG GTGCTGCTTGTGAGCTTGGGAGCCATCTCATTTTGGATGTGTTCAAATGGCAGCTTACAG TGTAGGATCTGCATA

TABLE 17  Codon Optimized Sequences Encoding H7 Hemagglutinin SEQ ID NO. Nucleic Acid Sequence 496 ATGAATACACAGATCCTTGTATTTGCCCTGATCGCAATCATTCCTACTAATGCTGACAAG ATTTGCCTCGGCCACCATGCGGTTAGTAATGGGACCAAAGTGAACACACTGACGGAGAGA GGAGTAGAGGTAGTTAACGCCACCGAGACTGTGGAGAGAACTAACATCCCACGGATTTGT TCCAAGGGTAAACGTACTGTGGATCTGGGGCAGTGCGGCTTGTTGGGTACCATCACTGGA CCGCCACAGTGCGACCAGTTTCTGGAGTTTTCCGCCGACCTGATTATAGAACGCCGAGAA GGCAGCGATGTCTGTTACCCCGGTAAATTCGTGAATGAAGAAGCCCTCCGCCAAATCCTG CGTGAGAGTGGGGGCATTGACAAAGAGGCGATGGGCTTTACATACAGCGGGATACGCACC AACGGCGCGACGTCAGCCTGCCGCAGGAGTGGAAGTTCTTTCTATGCCGAGATGAAGTGG CTGTTGTCTAATACTGATAATGCAGCCTTCCCCCAGATGACAAAGTCGTACAAGAACACC AGAAAGTCACCCGCACTCATTGTGTGGGGTATTCACCATTCTGTCTCTACTGCTGAGCAG ACGAAACTGTATGGTTCTGGGAACAAGCTCGTGACCGTGGGGTCCAGCAACTATCAGCAG AGCTTTGTGCCCTCCCCAGGAGAGAGGCCACAGGTGAATGGGTTGTCAGGCCGTATCGAT TTCCACTGGCTTATGTTGAATCCAAACGACACAGTGACATTTTCTTTCAACGGCGCCTTC ATTGCACCAGACAGAGCTAGCTTTCTGCGAGGGAAGAGTATGGGTATCCAGTCTGGTGTG CAGGTCGACGCTAACTGTGAGGGGGATTGCTACCATAGCGGGGGAACAATTATTTCAAAC CTGCCCTTCCAGAATATTGACAGCAGGGCAGTGGGAAAGTGCCCCCGCTATGTGAAACAG AGATCTTTGTTGCTGGCCACCGGCATGAAGAACGTTCCCGAAATTCCTAAGGGCCGGGGG CTTTTTGGGGCGATAGCCGGGTTCATTGAAAACGGGTGGGAGGGGCTAATCGATGGTTGG TACGGTTTTAGGCATCAAAACGCCCAGGGCGAAGGCACTGCGGCCGACTACAAATCCACA CAGAGCGCCATCGACCAAATCACTGGGAAACTTAACCGACTTATTGAGAAAACAAATCAA CAGTTTGAGCTGATTGATAACGAATTTAATGAGGTAGAGAAGCAGATCGGCAATGTAATA AACTGGACAAGGGACAGCATTACTGAAGTCTGGAGCTACAACGCCGAGTTGCTCGTCGCG ATGGAGAATCAGCATACCATCGATTTAGCCGACTCAGAGATGGATAAGCTGTATGAACGC GTAAAGAGGCAGCTGCGCGAGAACGCTGAAGAGGACGGGACTGGCTGCTTCGAAATTTTC CACAAATGCGATGATGATTGTATGGCTTCCATCCGGAACAATACCTACGACCATTCTAAG TACCGTGAAGAGGCCATGCAGAATAGGATCCAGATTGACCCAGTGAAGCTGAGCTCGGGT TATAAAGACGTGATTTTGTGGTTCAGTTTTGGCGCCTCTTGTTTTATCCTTCTGGCAATT GTTATGGGGTTGGTTTTCATCTGCGTCAAGAACGGCAACATGCGCTGTACTATTTGTATC 497 ATGAATACCCAGATTCTCGTCTTCGCACTGATAGCTATAATTCCAACCAATGCCGACAAG ATATGCTTGGGACACCATGCGGTGTCTAACGGCACAAAGGTGAATACTCTGACAGAGAGA GGAGTGGAGGTGGTTAACGCTACAGAGACTGTGGAAAGGACGAATATACCAAGGATATGC TCCAAGGGCAAGAAGACCGTCGACCTCGGCCAGTGTGGCCTGCTTGGCACTATCACAGGT CCCCCTCAATGCGATCAATTTCTGGAATTCTCTGCTGATCTGATAATCGAGCGCCGCGAG GGGTCTGACGTATGCTATCCCGGGAAATTCGTGAATGAGGAGGCTCTGAGACAGATATTG CGGGAGTCGGGGGGCATCGATAAAGAAGCTATGGGATTCACTTACTCGGGGATCAGAACA AACGGAGCTACATCTGCGTGTCGGCGGTCTGGCAGCTCGTTTTATGCCGAGATGAAGTGG CTGCTCTCCAATACAGACAATGCCGCATTCCCACAAATGACGAAAAGCTATAAAAATACT CGCAAGTCACCCGCACTAATCGTGTGGGGCATCCACCACAGCGTGTCCACCGCAGAGCAG ACCAAATTGTATGGTAGCGGCAATAAGCTGGTTACAGTGGGATCCTCCAACTACCAACAG TCCTTCGTCCCAAGCCCAGGGGCCCGACCGCAAGTTAACGGTCAGTCCGGACGCATTGAT TTTCACTGGCTGATGCTTAACCCAAACGACACAGTTACCTTTTCGTTTAACGGCGCTTTC ATTGCCCCAGATCGGGCCTCTTTTCTGCGGGGTAAGAGCATGGGAATCCAGTCGGGGGTA CAGGTCGACGCGAATTGTGAAGGCGATTGTTACCATTCTGGGGGCACTATTATATCAAAT CTTCCATTCCAGAATATTGACTCGCGCGCTGTGGGCAAATGCCCCAGGTACGTTAAGCAG CGATCACTGCTCCTCGCCACAGGTATGAAAAATGTTCCAGAGATTCCCAAGGGCAGGGGG CTGTTCGGTGCAATCGCCGGCTTTATAGAAAATGGGTGGGAGGGACTCATCGATGGTTGG TACGGTTTTAGGCATCAAAACGCCCAGGGGGAGGGGACGGCTGCCGATTACAAGTCTACC CAGTCAGCTATAGACCAGATCACTGGGAAACTAAACAGGCTGATCGAGAAAACCAACCAG CAGTTCGAACTGATTGACAACGAGTTCAACGAGGTTGAAAAGCAGATTGGTAACGTGATT AACTGGACCAGAGACTCTATCACCGAGGTCTGGAGCTACAATGCAGAACTACTTGTGGCT ATGGAAAACCAGCATACAATTGATCTTGCTGACTCTGAGATGGACAAGCTTTATGAGAGG GTGAAGAGACAGCTTCGGGAGAACGCTGAGGAGGATGGAACCGGTTGTTTCGAGATCTTT CACAAATGCGATGACGATTGCATGGCTAGCATTAGGAATAACACCTATGACCACTCTAAA TACAGAGAGGAGGCTATGCAGAATCGCATCCAGATCGACCCAGTGAAGCTGTCCTCTGGA TACAAGGACGTAATCCTGTGGTTCTCATTTGGGGCTTCGTGCTTCATCTTGCTGGCGATT GTTATGGGCTTAGTGTTTATCTGCGTTAAAAACGGGAACATGCGGTGTACAATCTGTATC 498 ATGAACACACAGATTCTGGTCTTTGCCTTGATCGCAATAATTCCAACTAATGCCGACAAA ATTTGTTTAGGTCATCACGCCGTTTCAAATGGAACTAAGGTCAACACCCTGACCGAGAGG GGCGTCGAGGTCGTGAATGCCACAGAAACTGTGGAGAGAACCAACATCCCTCGCATCTGT AGCAAGGGCAAGAAGACTGTCGATCTTGGACAGTGCGGTCTCCTGGGAACGATTACAGGC CCCCCACAGTGCGACCAATTCCTAGAATTCTCTGCCGACTTAATCATCGAAAGGCGTGAG GGATCTGACGTGTGCTATCCGGGAAAGTTCGTGAATGAGGAGGCCCTACGGCAGATTCTG CGGAAATCCGGAGGTATAGACAAAGAGGCAATGGGCTTCACCTACAGTGGGATACGCACA AATGGGGCCACATCCACTTGTCGGAGAAGCGGCTCTTCCTTTTATGCCGAGATGAAGTGG CTCTTATCCAACACAGACAATGCCGCCTTCCCTCAGATGACGAAGAGCTACAAAAACACC AGGAAGTCTCCAGCAATCATTGTTTGGGGCATCCACCATAGCGTCTCCACCGCTGAGCAA ACCAAATTATATGGGTCCGGGAATAAATTGGTCACAGTCGGTAGCTCCAACTACCAGCAG TCATTTGTCCCCTCACCGGGGGCTCGCCCACAAGTAAATGGTTTGTCTGGCAGAATCGAC TTTCATTGGCTCATGCTCAATCCAAACGACACGGTGACTTTCAGCTTTAACGGGGCATTT ATTGCCCCCGACCGAGCATGTTTTCTTAGAGGCAAAAGCATGGGGATTCAGAGCGGAGTC CAGGTCGACGCGGATTGCGAGGGTGACTGCTACCACTCAGGGGGTACCATTATCTCCAAC CTTCCTTTTCAGAATATCGATTCGAGAGCTGTGGGCAAGTGCCCTCGGTATGTTAAACAG CGATCCCTCCTTCTGGCCACTGGTATGAAGAACGTGCCTGAGATACCCAAAGGGAGGGGC CTGTTTGGGGCTATCGCTGGATTTATTGAGAATGGTTGGGAGGGCCTTATCGACGGCTGG TACGGCTTTAGGCACCAGAACGCGCAGGGCGAAGGCACAGCTGCCGACTACAAAAGCACC CAGAGCGCGATTGACCAGATCACCGGCAAATTGAACAGGCTTATCGAAAAAACGAACCAA CAGTTTGAGCTAATTGACAATGAGTTTAACGAGGTCGAGAGGCAGATTGGGAACGTCATC AACTGGACAAGAGACAGCATTACCGAGGTGTGGTCTTACAATGCAGAGTTGCTAGTGGCC ATGGAAAACCAACATACGATCGACCTCGCGGATTCTGAGATGGATAAGCTCTATGAAAGG GTGAAAAGGCAGCTGCGGGAAAATGCTGAGGAAGACGGAACAGGATGTTTTGAAATCTTC CACAAATGTGATGATGACTGTATGGCCTCTATAAGGAACAACACCTATGATCATTCCAAG TATCGAGAAGAGGCCATGCAGAACCGTATCCAGATTGACCCTGTAAAACTCAGTTCAGGG TACAAGGATGTGATCCTGTGGTTCAGCTTTGGCGCAAGCTGTTTCATTCTTCTCGCGATT GTGATGGGGCTAGTGTTCATTTGTGTGAAAAATGGAAATATGAGATGTACCATTTGTATC 499 ATGAACACCCAGATTCTGGTCTTCGCTCTGATTGCTATTATCCCAACCAATGCAGACAAG ATCTGTCTGGGGCACCATGCTGTGTCGAACGGCACGAAAGTGAACACACTGACCGAAAGA GGAGTCGAGGTGGTGAACGCGACCGAGACAGTGGAGCGGACAAACATCCCACGTATCTGC TCCAAGGGCAAGCGTACAGTGGACTTGGGGCAATGTGGCCTCCTTGGAACGATCACAGGA CCACCGCAGTGCGACCAGTTTCTGGAGTTTTCTGCCGATTTAATCATCGAAAGGCGGGAG GGTTCCGACGTTTGTTACCCGGGGAAGTTCGTTAACGAGGAAGCCCTGAGACAGATCCTA CGTGAGAGCGGCGGTATCGACAAGGAGGCTATGGGCTTTACATATAGCGGAATTAGAACA AACGGCGCTACCAGCGCCTGCCGCCGCAGCGGTTCATCTTTTTATGCCGAAATGAAGTGG CTGCTCTCCAACACCGACAACGCCGCTTTTCCACAGATGACGAAATCCTATAAGAATACC AGGAAAAGTCCAGCTCTGATTGTGTGGGGGATACACCACTCTGTGTCAACAGCGGAACAG ACAAAGCTCTATGGAAGCGGAAACAAACTCGTAACGGTCGGCAGTTCCAACTATCAGCAA TCCTTTGTGCCAAGTCCAGGCGCGCGTCCTCAGGTGAACGGCCTAAGTGGGAGAATCGAT TTCCATTGGTTAATGCTTAATCCAAATGACACCGTGACCTTTAGCTTTAACGGCGCCTTT ATTGCTCCCGACCGAGCTTCTTTCCTTAGAGGTAAGTCAATGGGTATCCAGAGCGGCGTG CAGGTTGACGCAAACTGTGAAGGCGATTGTTACCACTCCGGAGGCACTATCATTAGCAAC TTGCCATTTCAGAACATAGATTCACGCGCTGTGGGAAAGTGCCCTAGGTACGTGAAGCAG AGGTCCCTGTTGCTCGCTACGGGCATGAAGAACGTGCCAGAGATTCCCAAAGGCAGAGGG TTGTTCGGTGCCATTGCTGGTTTCATTGAGAATGGTTGGGAGGGCCTGATCGACGGGTGG TACGGTTTCCGTCACCAGAATGCTCAAGGGGAGGGTACAGCAGCCGACTATAAATCCACC CAGAGCGCAATCGATCAAATTACCGGCAAGCTAAATAGGCTGATTGAAAAAACTAATCAG CAGTTCGAGCTCATAGACAATGAGTTCAACGAAGTGGAAAAGCAGATTGGCAACGTCATC AATTGGACCAGAGATTCCATCACCGAGGTGTGGTCTTATAATGCCGAGCTGTTGGTTGCC ATGGAAAATCAGCATACAATAGACCTGGCCGACTCCGAAATGGATAAACTGTACGAGAGG GTTAAACGCCAACTGCGTGAGAATGCAGAGGAAGACGGAACAGGTTGTTTCGAGATCTTT CACAAATGCGACGACGACTGCATGGCCTCCATAAGGAATAATACATATGATCATAGCAAA TACAGGGAGGAGGCAATGCAAAACCGGATTCAGATTGATCCTGTGAAGCTGAGCAGCGGC TACAAGGACGTTATTCTTTGGTTCAGTTTCGGTGCATCATGCTTCATACTCCTGGCAATA GTGATGGGTCTGGTGTTCATCTGCGTGAAAAACGGAAATATGAGGTGCACCATATGCATC 500 ATGAATACCCAAATACTCGTCTTTGCTCTCATCGCTATCATTCCTACGAATGCCGACAAA ATATGCCTAGGACATCACGCCGTGAGCAATGGGACAAAGGTGAATACCTTAACCGAAAGA GGCGTGGAGGTCGTGAACGCCACAGAGACTGTGGAGCGCACCAATATACCTAGAATCTGC TCAAAGGGCAAGAAAACAGTGGACCTAGGACAGTGTGGGCTTCTGGGGACGATCACTGGG CCACCACAGTGCGACCAGTTCCTGGAGTTCAGCGCGGACCTGATCATCGAACGCCGAGAG GGCTCTGATGTGTGCTACCCTGGCAAGTTTGTGAACGAGGAGGCTCTTAGGCAGATTCTC AGGGAATCCGGCGGAATTGACAAGGAAGCTATGGGCTTCACTTATAGTGGAATCCGCACC AATGGGGCAACGTCCGCTTGTAGGAGATCCGGGAGCAGTTTTTATGCAGAAATGAAATGG CTGCTTAGTAACACGGACAACGCCGCTTTTCCGCAGATGACTAAGTCCTACAAGAACACC CGCAAATCACCAGCTCTGATTGTGTGGGGGATTCACCATTCCGTGAGCACAGCCGAGCAG ACAAAGTTGTATGGCTCTGGAAATAAACTCGTGACTGTGGGCAGTTCGAACTACCAGCAG TCTTTTGTGCCTTCTCCCGGAGCCCGTCCCCAGGTCAACGGGCAGTCCGGAAGAATTGAT TTCCACTGGTTGATGCTCAACCCGAATGATACAGTGACTTTTAGCTTCAACGGCGCTTTT ATTGCCCCTGATCGTGCCAGCTTCCTTAGGGGCAAATCCATGGGGATTCAGTCAGGAGTT CAGGTAGATGCCAATTGTGAGGGAGATTGTTACCACTCAGGGGGTACGATCATCAGCAAC TTGCCATTTCAGAACATCGACAGTCGGGCAGTGGGCAAATGCCCACGTTACGTGAAGCAA CGGAGTCTCCTGTTAGCCACAGGGATGAAAAATGTTCCAGAGATCCCTAAGGGCCGGGGA CTGTTCGGGGCCATTGCCGGATTTATCGAGAATGGATGGGAGGGACTTATTGATGGTTGG TACGGCTTTCGGCATCAGAATGCCCAAGGGGAGGGCACAGCTGCCGACTATAAATCAACC CAGTCTGCAATAGATCAAATCACCGGTAAGCTGAATCGCCTTATCGAAAAAACGAACCAA CAATTCGAGCTGATCGATAACGAATTCAATGAAGTGGAGAAACAGATTGGGAATGTTATT AACTGGACAAGAGACAGCATAACCGAAGTCTGGTCCTATAATGCCGAGTTACTTGTGGCC ATGGAAAACCAGCATACGATTGACTTAGCCGACTCCGAGATGGACAAGTTGTATGAGCGG GTGAAGAGACAGTTACGGGAGAACGCCGAAGAGGACGGGACTGGTTGTTTTGAAATCTTC CATAAGTGTGACGACGACTGCATGGCCAGTATTCGCAATAACACCTACGACCATAGCAAG TACAGGGAAGAAGCCATGCAGAATCGTATTCAGATCGATCCTGTCAAACTTAGTAGTGGG TACAAGGACGTTATCCTGTGGTTTTCTTTTGGGGCCTCCTGTTTCATTCTTCTGGCTATT GTAATGGGACTGGTTTTCATATGTGTGAAAAATGGTAACATGCGGTGCACTATATGTATC 501 ATGAATACTCAGATTCTAGTGTTCGCTTTGATAGCTATAATCCCAACCAACGCCGACAAA ATATGCCTGGGGCACCACGCAGTATCCAACGGGACCAAGGTCAATACCCTGACCGAACGG GGTGTGGAAGTCGTGAACGCCACAGAGACCGTTGAGAGAACAAACATCCCTAGAATTTGT AGCAAAGGGAAGAGGACTGTCGACTTGGGGCAGTGCGGGTTACTGGGAACAATCACTGGC CCACCCCAGTGTGACCAGTTCCTCGAGTTCTCTGCTGATCTTATCATTGAGAGAAGAGAG GGCAGTGACGTGTGTTATCCTGGAAAATTCGTAAACGAGGAGGCGCTTAGGCAGATTCTG CGCGAATCAGGAGGTATCGATAAAGAGGCAATGGGGTTTACTTACAGCGGTATCCGAACC AACGGCGCTACATCTGCATGCCGCAGGTCTGGCTCATCTTTCTATGCAGAGATGAAGTGG TTGCTCTCTAACACCGATAATGCGGCATTTCCTCAGATGACCAAGAGCTACAAGAACACC AGAAAATCCCCCGCGTTGATCGTGTGGGGCATCCACCATTCAGTGTCCACCGCTGAGCAG ACAAAACTCTACGGATCTGGGAACAAGTTGGTGACTGTGGGGTCCTCTAACTACCAGCAA TCGTTTGTGCCATCCCCAGGGGCTAGACCCCAGGTCAACGGTCTCTCTGGCCGGATCGAC TTCCACTGGCTTATGCTTAACCCAAACGATACCGTCACCTTTAGCTTTAATGGTGCTTTC ATTGCCCCCGACCGGGCAAGCTTCTTACGAGGCAAGAGTATGGGAATACAGAGTGGGGTT CAAGTGGATGCCAACTGCGAGGGCGACTGTTACCACAGCGGCGGCACCATAATTTCAAAT CTGCCGTTCCAGAATATAGACTCTCGAGCTGTTGGGAAGTGCCCCCGATACGTAAAGCAG CGCTCTCTGTTACTGGCCACCGGCATGAAAAATGTTCCTGAGATACCGAAGGGACGTGGC CTCTTCGGGGCCATCGCCGGGTTCATCGAGAACGGCTGGGAAGGACTGATCGATGGATGG TACGGATTCAGGCATCAGAATGCTCAGGGAGAAGGGACGGCTGCAGATTATAAGTCTACA CAGTCCGCCATCGATCAGATCACCGGTAAGCTTAATAGAATCATAGAGAAGACGAACCAG CAGTTCGAGCTGATCGATAACGAGTTTAATGAGGTCGAAAAGCAGATTGGCAACGTGATA AATTGGACAAGAGACAGTATTACTGAAGTGTGGTCCTACAACGCCGAGCTTTTGGTGGCC ATGGAAAACCAACACACCATCGACTTAGCAGATTCCGAGATGGATAAACTTTACGAGCGA GTAAAAAGACAGCTCAGGGAGAATGCTGAAGAAGACGGCACAGGATGTTTCGAGATTTTC CACAAGTGTGATGACGATTGCATGGCATCAATTCGCAACAACACTTACGATCATAGCAAG TATCGCGAGGAGGCCATGCAGAACCGCATCCAAATTGATCCTGTCAAGCTAAGTTCCGGG TATAAAGACGTGATTTTGTGGTTTTCTTTTGGCGCTAGCTGCTTTATTCTACTGGCTATT GTCATGGGCTTGGTTTTCATCTGCGTGAAAAATGGCAATATGCGCTGCACTATATGTATC 502 ATGAATACACAAATTCTGGTCTTCGCCTTGATTGCCATTATACCAACTAATGCCGATAAG ATTTGCCTCGGGCACCATGCCGTCTCCAATGGCACAAAAGTCAACACACTGACTGAACGA GGGGTCGAGGTGGTCAACGCCACTGAAACCGTGGAAAGGACCAACATCCCCCGCATTTGC AGCAAGGGTAAAAAAACGGTAGACCTGGGACAGTGTGGGCTGCTAGGTACTATTACCGGC CCCCCACAATGTGACCAATTCTTAGAGTTCTCCGCTGACTTGATAATTGAACGGAGAGAG GGTTCTGACGTGTGCTACCCTGGGAAGTTTGTAAATGAAGAAGCCCTTCGACAGATTCTC AGGGAGTCCGGCGGTATTGATAAGGAGGCCATGGGATTTACGTACAGCGGAATTCGGACT AATGGGGCCACTTCGGCCTGCCGGCGCTCTGGTTCCTCCTTTTATGCAGAGATGAAATGG CTCCTATCCAACACGGATAACGCCGCCTTCCCACAGATGACAAAATCCTACAAGAACACT CGGAAGAGCCCAGCGCTGATTGTGTGGGGTATTCACCATAGCGTGTCCACTGCCGAGCAG ACGAAGCTGTACGGAAGTGGCAACAAATTGGTCACTGTAGGCTCATCTAATTACCAGCAG AGCTTTGTTCCTTCCCCTGGGGCAAGGCCACAAGTGAATGGCCAAAGTGGTAGAATCGAT TTCCACTGGCTCATGTTGAATCCTAATGACACGGTAACTTTCAGTTTCAACGGCGCTTTC ATTGCACCCGACCGGGCTTCATTTCTCCGGGGGAAGTCCATGGGGATCCAGTCAGGAGTC CAGGTCGATGCTAATTGTGAAGGCGATTGTTACCACTCCGGTGGGACCATCATTAGCAAT CTGCCATTTCAGAACATCGATTCCAGAGCAGTCGGCAAGTGCCCTAGATATGTGAAGCAG AGGAGCCTGCTGCTAGCTACGGGTATGAAAAATGTGCCAGAGATCCCAAAGGGGCGGGGT CTTTTCGGTGCCATAGCTGGATTTATCGAGAATGGCTGGGAGGGTCTGATCGACGGATGG TACGGGTTCAGGCATCAGAATGCCCAGGGGGAGGGCACTGCCGCCGACTATAAGTCTACA CAAAGCGCTATTGACCAAATTACCGGTAAGCTGAACAGACTGATCGAGAAGACAAACCAG CAGTTCGAGCTCATCGATAATGAATTCAACGAGGTAGAAAAGCAAATCGGCAACGTGATT AACTGGACCAGGGATTCTATCACTGAGGTGTGGTCATACAACGCGGAGCTGCTCGTTGCC ATGGAAAATCAGCACACTATTGACCTGGCCGACAGCGAAATGGACAAGCTGTACGAAAGA GTGAAACGACAGCTGCGGGAGAACGCCGAAGAGGACGGGACTGGTTGTTTCGAAATCTTC CATAAGTGCGATGACGACTGTATGGCTTCAATCAGGAACAACACATACGACCACTCTAAG TACAGAGAGGAGGCTATGCAGAATCGTATCCAGATTGACCCTGTAAAACTCTCCTCTGGG TACAAAGACGTGATCCTGTGGTTTTCGTTCGGCGCATCCTGCTTCATCCTGCTCGCGATC GTCATGGGATTAGTGTTCATTTGCGTCAAAAATGGCAATATGAGGTGTACCATTTGCATC 503 ATGAATACTCAGATCCTAGTGTTTGCTCTCATTGCTATAATCCCCACAAATGCTGACAAG ATCTGCTTGGGCCATCACGCCGTGAGTAACGGCACTAAGGTGAATACGCTGACGGAACGG GGTGTAGAAGTTGTAAACGCCACCGAAACAGTCGAAAGGACAAACATCCCGCGCATCTGC AGTAAAGGTAAAAAGACCGTTGACCTCGGCCAATGCGGACTGCTGGGGACTATCACCGGA CCCCCCCAATGTGATCAATTTCTGGAGTTCAGTGCGGACTTGATAATCGAAAGACGGGAA GGTTCCGATGTGTGCTATCCAGGCAAGTTCGTTAATGAGGAAGCACTCCGGCAAATTCTT CGGGAAAGCGGGGGCATAGACAAGGAAGCCATGGGCTTTACTTACAGCGGAATCCGCACA AACGGAGCAACATCCGCTTGCAGGAGAAGTGGTAGTTCTTTTTATGCCGAGATGAAATGG TTGCTGAGCAATACCGACAACGCAGCCTTTCCACAGATGACCAAGAGCTACAAAAATACA AGAAAGTCCCCAGCTCTGATTGTGTGGGGAATACACCATAGCGTTAGCACAGCCGAACAA ACAAAGCTGTACGGTTCAGGAAATAAACTTGTGACGGTAGGATCCAGCAATTATCAGCAA TCTTTCGTGCCATCACCAGGCGCTCGGCCTCAGGTCAACGGGCAGTCGGGCCGTATAGAT TTTCATTGGCTGATGCTGAATCCTAATGATACTGTGACCTTTAGCTTTAACGGGGCGTTC ATAGCCCCCGATCGGGCATCTTTTCTCAGGGGTAAAAGCATGGGTATTCAGAGTGGAGTG CAGGTTGACGCCAATTGCGAGGGAGATTGCTATCATTCCGGCGGGACCATTATTTCCAAC CTCCCCTTCCAGAACATCGACAGCCGAGCTGTCGGCAAATGCCCCAGGTATGTGAAACAA CGCAGCCTGTTGTTAGCAACAGGGATGAAGAATGTTCCTGAAATTCCAAAAGGGCGAGGT CTGTTCGGCGCTATCGCAGGGTTCATTGAGAACGGTTGGGAGGGCCTGATCGATGGCTGG TATGGCTTTAGGCACCAAAACGCACAGGGCGAAGGGACTGCCGCAGACTACAAATCTACA CAGTCAGCGATTGATCAAATCACTGGCAAACTGAACCGCCTCATTGAGAAGACCAACCAG CAGTTCGAACTGATAGACAATGAGTTCAATGAGGTTGAAAAGCAGATAGGTAATGTGATA AATTGGACCAGAGATAGTATAACTGAAGTCTGGTCCTATAACGCCGAGTTACTTGTCGCT ATGGAGAACCAGCACACAATTGACCTGGCGGACAGCGAGATGGATAAGCTGTACGAACGC GTAAAAAGACAACTGCGCGAGAATGCGGAGGAGGACGGCACCGGGTGTTTCGAGATCTTT CACAAGTGTGATGATGATTGTATGGCCTCCATTAGAAACAACACCTATGATCACTCCAAA TACCGGGAGGAAGCAATGCAGAACCGCATACAGATTGACCCCGTCAAGTTGAGTTCCGGG TATAAAGACGTGATACTCTGGTTCAGTTTTGGTGCCTCTTGCTTTATCCTGCTTGCCATC GTGATGGGACTGGTGTTTATTTGCGTTAAAAACGGGAATATGCGTTGTACGATTTGTATA 504 ATGAATACCCAGATTCTTGTGTTCGCCCTCATTGCCATCATCCCCACCAATGCCGACAAG ATTTGCTTGGGACATCACGCTGTGAGTAATGGCACAAAAGTAAATACGTTAACCGAACGC GGGGTTGAAGTGGTGAATGCTACAGAGACGGTAGAGCGCACAAACATCCCGAGAATTTGC TCCAAAGGCAAAAAGACTGTTGACCTTGGCCAGTGCGGGCTGCTGGGTACGATTACTGGG CCACCTCAGTGCGATCAGTTCCTAGAATTTTCAGCAGATTTAATCATCGAAAGACGTGAA GGATCAGATGTGTGTTATCCCGGAAAGTTCGTGAATGAGGAGGCTTTGAGACAGATCTTG CGTGAATCTGGGGGCATAGATAAGGAAGCCATGGGGTTTACTTATTCTGGAATCCGCACT AATGGGGCCACCAGCGCATGTAGGCGCTCCGGATCCTCATTCTATGCCGAGATGAAGTGG CTTCTCAGTAACACAGATAATGCCGCCTTCCCCCAAATGACAAAGAGCTACAAGAATACA CGGAAAAGCCCCGCCCTGATCGTATGGGGGATTCATCATTCTGTTAGCACTGCCGAGCAA ACCAAACTGTACGGCTCAGGAAATAAGCTCGTGACGGTAGGGTCATCAAACTACCAGCAG AGCTTCGTACCTTCCCCCGGCGCTAGACCTCAGGTCAACGGTCAGTCCGGACGAATTGAT TTCCACTGGTTAATGCTCAACCCAAATGACACCGTCACATTCAGTTTTAACGGTGCCTTT ATTGCTCCTGACAGAGCCTCTTTTCTGAGGGGCAAGTCCATGGGCATCCAGAGCGGGGTA CAGGTCGACGCCAATTGCGAGGGCGACTGCTACCATTCAGGGGGGACGATCATTAGTAAC TTACCCTTTCAAAACATTGATTCACGGGCCGTAGGCAAGTGTCCGAGATACGTCAAGCAG CGGAGCTTGCTGTTGGCAACTGGCATGAAAAACGTTCCCGAAATCCCTAAGGGCCGAGGT CTTTTTGGGGCAATTGCGGGCTTCATAGAGAATGGTTGGGAGGGACTGATCGATGGGTGG TATGGCTTCAGACATCAGAACGCACAGGGTGAGGGTACCGCTGCTGACTATAAGAGCACC CAGAGCGCAATAGATCAGATCACTGGCAAGCTTAACCGACTTATCGAAAAGACCAACCAG CAGTTTGAATTGATTGACAACGAATTTAACGAAGTTGAGAAGCAAATTGGGAACGTTATT AATTGGACAAGGGATTCCATCACAGAGGTTTGGAGTTACAATGCGGAGTTATTAGTGGCA ATGGAGAACCAACATACTATTGACCTTGCGGATAGCGAGATGGACAAGCTGTACGAGAGG GTCAAGCGCCAGTTACGGGAAAACGCGGAAGAGGATGGAACTGGATGTTTCGAGATCTTC CACAAATGCGATGACGATTGCATGGCGTCGATCCGAAACAATACCTACGATCACAGTAAA TACAGGGAAGAGGCAATGCAGAACCGAATTCAGATTGATCCCGTGAAGCTCAGCTCAGGG TACAAGGACGTGATTCTGTGGTTTTCATTTGGAGCTAGCTGCTTTATACTGCTGGCTATT GTTATGGGCTTGGTATTCATCTGTGTGAAGAATGGTAACATGAGGTGTACAATTTGCATT 505 ATGAATACTCAGATCCTGGTGTTTGCTCTGATAGCTATCATCCCCACCAACGCCGATAAG ATTTGCCTGGGCCACCACGCAGTGAGTAACGGGACAAAAGTCAACACTCTAACTGAGCGC GGCGTTGAAGTTGTAAATGCCACTGAAACTGTTGAGAGAACTAATATACCCCGCATTTGC TCAAAAGGCAAGAGGACTGTGGATCTCGGCCAGTGTGGGCTTCTGGGGACCATAACTGGT CCGCCCCAATGTGACCAGTTCTTGGAGTTTTCCGCAGACCTAATTATCGAGCGTCGCGAA GGCTCCGATGTGTGCTACCCCGGCAAGTTTGTCAATGAAGAAGCCCTGAGGCAGATTCTG CGAGAAAGCGGGGGTATAGACAAAGAAGCTATGGGCTTTACTTATAGCGGAATTCGTACA AACGGCGCTACATCCGCCTGTCGACGGTCTGGTTCTAGCTTCTATGCTGAGATGAAATGG TTGCTTAGCAACACAGACAATGCCGCTTTCCCCCAGATGACTAAAAGTTATAAAAATACC CGGAAGAGCCCCGCACTTATCGTATGGGGGATCCATCACAGTGTGTCGACTGCCGAACAG ACCAAGCTCTACGGGAGCGGCTCCAAGCTGGTGACAGTGGGGTCTTCTAATTACCAACAA TCCTTTGTCCCTTCCCCTGGCGCCCGCCCCCAAGTGAATGGGCTAAGCGGAAGGATTGAC TTTCATTGGCTGATGCTGAATCCCAACGATACAGTGACGTTCAGCTTTAACGGGGCGTTT ATTGCCCCTGACCGTGCAAGTTTTCTCCGCGGGAAATCCATGGGCATCCAAAGCGGCGTC CAAGTGGATGCAAACTGCGAAGGAGACTGCTATCACTCTGGAGGAACTATTATTTCTAAC CTGCCTTTCCAGAACATCGACTCAAGGGCCGTGGGGAAATGCCCGCGCTATGTTAAACAG AGAAGCCTGTTGCTTGCCACAGGTATGAAGAACGTGCCCGAGATCCCTAAGGGCAGAGGG CTGTTCGGCGCAATCGCAGGGTTCATTGAAAACGGATGGGAGGGCCTCATCGACGGATGG TACGGTTTTCGGCACCAAAACGCACAGGGGGAGGGCACAGCGGCGGATTATAAGAGCACT CAGAGTGCCATAGATCAGATTACGGGGAAGCTCAATAGACTTATAGAGAAGACCAATCAG CAATTCGAGCTGATCGATAACGAGTTCAATGAGGTAGAAAAGCAGATTGGGAATGTCATC AACTGGACAAGAGATAGTATAACAGAGGTGTGGAGCTACAACGCCGAGTTACTTGTGGCC ATGGAAAACCAGCACACAATCGACCTGGCTGATAGCGAAATGGACAAGCTGTATGAAAGA GTCAAGAGACAGCTTCGAGAAAACGCAGAGGAGGACGGAACCGGCTGCTTCGAGATTTTT CACAAATGTGACGATGATTGCATGGCGTCAATCCGGAACAACACCTATGACCACTCTAAG TATCGAGAGGAGGCGATGCAGAACCGGATACAGATCGATCCTGTTAAGCTTTCATCAGGT TACAAGGACGTAATCCTGTGGTTCTCGTTCGGCGCATCCTGCTTTATCCTTCTGGCAATT GTGATGGGGCTCGTATTCATCTGCGTGAAAAATGGCAATATGAGATGTACTATTTGCATT 506 ATGAATACACAGATCCTTGTGTTCGCACTGATCGCGATTATCCCCACCAACGCAGACAAG ATCTGTTTAGGCCACCATGCTGTGAGCAATGGGACAAAAGTCAACACGCTGACAGAGCGG GGAGTGGAGGTGGTAAACGCTACTGAAACGGTCGAGAGAACTAACATTCCTAGAATTTGT TCAAAAGGGAAAAGGACCGTGGATCTGGGCCAGTGTGGGCTGCTGGGAACAATCACTGGG CCACCACAATGCGATCAGTTTTTAGAGTTCTCGGCCGACCTAATCATAGAGCGCAGAGAG GGCTCCGATGTATGCTATCCCGGGAAGTTTGTGAATGAAGAAGCTTTAAGGCAGATTCTT AGAGAATCCGGTGGGATTGACAAGGAGGCAATGGGGTTTACATACTCCGGTATTAGAACA AACGGGGCCACCTCCGCGTGCAGGAGAAGCGGCTCCTCTTTTTATGCTGAGATGAAATGG CTGCTGTCAAACACCGACAACGCCGCATTTCCCCAAATCACCAAGTCCTACAAGAATACA AGAAAGTCTCCAGCCCTGATTGTTTGGGGGATACACCACTCAGTGTCCACCGCTGAACAG ACCAAGTTGTATGGTAGCGGAAACAAGCTGGTGACCGTCGGGTCCTCAAATTATCAGCAG TCATTTGTCCCATCTCCGGGCGCTAGGCCTCAGGTGAATGGGCTGAGTGGACGCATTGAC TTCCACTGGCTTATGCTGAATCCTAATGACACAGTTACATTTAGTTTCAACGGGGCATTT ATTGCGCCAGATAGAGCCAGTTTCTTGCGCGGCAAATCTATGGGAATCCAGAGCGGCGTT CAAGTGGACGCCAACTGTGAGGGGGACTGCTACCACAGCGGCGGGACAATTATCAGCAAC CTGCCATTCCAGAATATTGATTCACGGGCTGTGGGAAAGTGTCCTAGGTACGTCAAACAG CGGTCTCTGCTGTTAGCAACCGGAATGAAGAATGTACCCGAGATCCCTAAAGGCCGAGGG TTGTTCGGCGCAATTGCGGGCTTCATTGAGAATGGTTGGGAGGGTCTCATCGATGGTTGG TACGGCTTCAGACACCAGAATGCCCAAGGCGAAGGAACTGCAGCCGACTATAAGTCAACT CAAAGCGCAATCGACCAGATCACAGGGAAACTGAATCGCTTGATCGAAAAGACCAACCAG CAATTCGAGCTGATCGACAATGAGTTTAACGAGGTCGAGAAGCAGATCGGAAATGTGATT AATTGGACTCGAGACTCAATTACCGAGGTTTGGAGTTACAATGCCGAACTGCTGGTGGCC ATGGAGAATCAACATACCATAGATCTCGCCGATAGCGAGATGGATAAACTGTATGAACGA GTTAAGCGACAACTGAGAGAAAACGCCGAAGAAGACGGAACCGGGTGCTTTGAAATCTTC CACAAATGCGATGATGATTGTATGGCTTCAATTCGCAACAACACCTACGATCACAGCAAG TACCGAGAAGAGGCCATGCAAAACCGGATTCAAATCGATCCAGTGAAGCTGAGTTCTGGA TATAAGGATGTGATTCTGTGGTTTTCATTTGGGGCTAGCTGTTTCATTCTTCTTGCCATC GTGATGGGTCTCGTGTTTATTTGTGTCAAGAATGGGAACATGCGCTGCACGATATGCATC 507 ATGAACACCCAAATTCTAGTTTTCGCCCTTATCGCCATCATACCGACAAACGCAGACAAA ATATGTCTCGGACACCACGCGGTGAGTAATGGCACCAAGGTGAACACTCTTACCGAGCGA GGGGTGGAGGTGGTGAATGCAACAGAAACCGTGGAGCGCACCAACATCCCCCGGATTTGT TCAAAGGGAAAAAAGACAGTCGACCTGGGGCAGTGTGGGCTCCTGGGCACTATCACTGGG CCCCCGCAGTGCGACCAATTCCTGGAGTTTAGCGCAGACCTGATCATCGAAAGAAGGGAG GGGTCAGACGTGTGTTACCCGGGAAAGTTCGTGAACGAAGAGGCACTTCGCCAGATATTA AGAGAGAGCGGCGGGATTGATAAAGAAGCTATGGGCTTCACCTATTCTGGCATTAGGACC AATGGCGCCACAAGTGCCTGTAGGAGATCAGGCTCGAGCTTCTACGCTGAGATGAAATGG CTCCTGTCGAACACAGACAACGCCGCTTTTCCTCAGATGACGAAATCCTATAAAAACACG CGGAAGTCTCCTGCGCTCATTGTGTGGGGAATTCATCACAGTGTGTCTACCGCTGAGCAG ACAAAGCTTTACGGTTCCGGAAATAAATTAGTGACAGTTGGCTCTAGTAACTATCAGCAA AGTTTCGTACCATCCCCGGGAGCGAGACCGCAGGTAAATGGACAGTCCGGGCGGATAGAT TTCCATTGGCTCATGCTGAATCCTAATGACACCGTCACATTCAGCTTTAACGGGGCATTC ATCGCACCCGATCGAGCTAGTTTTCTTCGCGGCAAGTCTATGGGAATTCAATCTGGCGTA CAGGTGGATGCCAATTGCGAGGGTGATTGCTACCACTCTGGCGGTACCATCATCTCGAAC CTCCCTTTTCAAAACATCGATAGCAGAGCCGTGGGCAAGTGCCCTCGATATGTTAAGCAG AGAAGCCTGCTGCTCGCAACCGGCATGAAGAACGTGCCTGAGATTCCTAAGGGCCGCGGC TTATTCGGCGCCATTGCTGGCTTCATCGAAAATGGCTGGGAAGGTTTAATCGATGGATGG TATGGGTTCCGCCATCAGAACGCTCAAGGTGAGGGCACTGCCGCCGATTACAAAAGCACC CAGAGTGCAATCGACCAGATTACTGGTAAGCTTAATCGACTAATTGAGAAAACCAACCAG CAGTTCGAACTGATTGATAACGAGTTTAATGAAGTCGAGAAGCAGATTGGAAACGTTATC AATTGGACCCGAGACAGTATAACTGAGGTGTGGAGCTACAACGCCGAGCTCCTCGTGGCT ATGGAGAACCAACATACAATCGATCTTGCAGATTCTGAAATGGATAAGCTATACGAAAGA GTAAAGCGACAGCTCCGGGAAAACGCAGAGGAAGACGGAACTGGATGTTTCGAGATTTTT CACAAGTGCGACGACGATTGCATGGCAAGCATTAGAAATAACACATACGACCACTCAAAG TACCGCGAGGAGGCGATGCAGAATAGGATACAGATCGACCCTGTAAAGCTGAGCTCTGGG TACAAGGACGTGATCTTGTGGTTTTCTTTCGGCGCATCATGCTTCATCTTGCTGGCAATC GTGATGGGCCTGGTCTTTATTTGCGTAAAGAACGGCAATATGCGCTGTACAATCTGTATC 508 ATGAATACTCAGATACTGGTGTTCGCACTCATCGCAATTATACCCACTAATGCCGATAAG ATTTGTTTAGGACATCACGCCGTCAGTAACGGAACTAAGGTTAACACACTAACAGAGCGA GGCGTCGAAGTGGTTAATGCAACTGAGACGGTCGAGCGCACAAACATCCCTCGTATTTGC AGCAAAGGAAAGAAAACCGTCGATCTGGGACAGTGCGGACTCCTGGGGACCATAACCGGC CCTCCCCAGTGCGATCAGTTTCTGGAGTTCTCAGCAGATCTTATAATCGAGCGACGGGAA GGTTCCGACGTATGTTATCCCGGTAAATTCGTCAACGAAGAAGCCCTGAGACAGATCCTG CGGGAGAGTGGAGGAATTGACAAGGAGGCCATGGGATTTACCTACAGCGGCATTAGAACG AATGGGGCCACATCTGCCTGCCGACGCAGCGGCAGCTCATTCTACGCCGAGATGAAATGG TTACTGTCCAATACCGACAACGCCGCGTTCCCGCAGATGACCAAATCTTACAAGAACACT CGAAAATCCCCCGCACTTATTGTGTGGGGCATCCACCATAGTGTGTCAACCGCTGAGCAG ACTAAACTCTACGGTTCTGGTAACAAACTCGTGACTGTGGGAAGCTCAAACTACCAGCAA AGCTTTGTGCCCTCTCCCGGGGCCAGGCCACAGGTGAACGGACAGTCCGGACGCATAGAC TTCCACTGGCTGATGCTAAATCCGAACGACACCGTCACCTTCAGTTTTAATGGGGCTTTC ATCGCCCCTGACAGAGCTAGCTTCCTGCGCGGTAAGAGCATGGGTATTCAGAGCGGGGTG CAGGTCGACGCCAACTGCGAAGGTGATTGCTATCATTCAGGGGGCACAATTATCTCCAAC CTCCCATTTCAGAACATCGATAGCCGCGCAGTCGGTAAGTGTCCACGATACGTTAAACAA AGGTCACTGCTCCTTGCCACTGGCATGAAAAACGTCCCGGAGATCCCGAAGGGCCGCGGA CTCTTTGGGGCCATCGCTGGGTTCATTGAAAATGGTTGGGAGGGGCTCATTGACGGATGG TATGGCTTTAGGCACCAGAACGCCCAAGGAGAGGGGACCGCAGCCGATTATAAGAGCACA CAGTCTGCCATTGACCAGATAACCGGTAAACTTAACCGGTTAATCGAAAAAACTAACCAG CAGTTCGAATTAATCGACAACGAATTTAATGAAGTCGAGAAACAGATCGGCAACGTCATC AACTGGACCCGAGATAGCATAACTGAAGTGTGGTCCTACAACGCCGAGCTGCTCGTGGCT ATGGAGAATCAGCATACCATCGACTTGGCCGACAGTGAAATGGATAAGCTGTACGAGAGA GTTAAGCGCCAGCTGAGAGAGAACGCAGAAGAGGACGGGACCGGCTGCTTTGAGATTTTC CATAAGTGCGATGACGACTGTATGGCAAGCATTCGCAATAATACTTACGATCACTCCAAA TATAGGGAGGAGGCCATGCAAAACCGCATTCAGATTGATCCGGTGAAGTTGTCAAGTGGA TATAAGGATGTGATTCTCTGGTTCTCCTTCGGGGCCTCCTGTTTTATTCTTCTCGCAATC GTTATGGGCTTGGTCTTCATCTGCGTAAAAAATGGGAATATGAGATGTACTATCTGTATC 509 ATGAACACACAAATTCTTGTATTTGCCCTTATAGCAATCATTCCAACCAACGCAGACAAG ATATGCCTGGGGCACCACGCCGTCTCTAACGGTACAAAGGTAAACACACTAACCGAACGC GGTGTCGAGGTAGTGAATGCAACTGAGACCGTGGAGCGGACCAACATACCAAGAATCTGC TCCAAAGGGAAGAGAACGGTGGATCTAGGACAGTGCGGGCTGCTCGGGACTATCACTGGA CCACCTCAGTGTGATCAATTTTTAGAGTTCTCGGCAGACTTAATCATCGAACGGCGGGAA GGATCTGATGTTTGCTACCCTGGCAAGTTTGTTAATGAAGAGGCGCTGCGACAGATTTTG CGCGAATCCGGTGGTATCGATAAAGAAGCAATGGGCTTCACTTATAGTGGCATTCGGACC AATGGAGCCACAAGCGCATGCCGAAGGAGCGGGTCCAGCTTTTACGCTGAAATGAAATGG CTCTTGAGTAATACAGATAACGCCGCCTTTCCTCAAATGACAAAAAGCTATAAGAATACG CGAAAAAGCCCTGCTCTAATCGTCTGGGGTATCCACCACTCTGTGTCTACAGCCGAACAA ACCAAGCTGTATGGCAGCGGCTCAAAGCTGGTAACAGTGGGATCAAGCAATTACCAGCAG AGTTTTGTGCCTAGCCCTGGAGCTAGACCGCAGGTGAACGGCCTTTCAGGTCGGATAGAC TTTCACTGGCTTATGTTAAATCCAAATGACACGGTGACCTTCTCTTTCAACGGGGCATTT ATCGCACCAGATAGGGCATCTTTTCTGCGGGGGAAGAGTATGGGCATCCAATCCGGAGTG CAGGTTGATGCAAATTGCGAGGGGGATTGTTATCACTCCGGCGGTACAATAATTAGTAAC CTCCCATTTCAGAATATTGATAGTCGTGCCGTCGGAAAATGTCCTCGCTATGTCAAGCAG AGATCGCTGTTACTTGCCACCGGCATGAAAAATGTGCCCGAAATCCCAAAGGGCCGAGGT CTGTTCGGGGCTATCGCAGGCTTCATTGAAAATGGATGGGAAGGCCTGATCGACGGGTGG TACGGCTTCCGTCATCAGAACGCACAGGGGGAAGGGACTGCAGCGGATTATAAGTCCACC CAAAGCGCTATTGACCAGATCACCGGCAAGCTCAATCGGCTCATAGAAAAAACTAATCAA CAGTTTGAGTTGATAGATAATGAGTTTAACGAGGTCGAGAAGCAGATTGGGAATGTGATC AATTGGACCAGAGACTCAATAACTGAGGTGTGGTCATACAATGCGGAGTTGTTGGTCGCT ATGGAAAATCAACACACAATCGACCTGGCTGACTCAGAAATGGATAAGCTGTACGAGCGG GTCAAGAGACAGCTGCGCGAGAATGCCGAGGAAGATGGAACAGGTTGCTTTGAAATTTTC CATAAATGCGATGATGACTGTATGGCAAGTATTCGGAACAATACTTACGATCACAGTAAG TATAGAGAAGAAGCAATGCAAAACAGAATTCAGATTGATCCGGTGAAGCTGAGCTCAGGA TACAAAGATGTTATCCTATGGTTTTCTTTTGGGGCCTCATGCTTTATCTTATTGGCCATA GTTATGGGGCTAGTATTTATCTGCGTAAAATCAAGGAATATGAGGTGCACCATCTGCATT 510 ATGAATACACAGATCTTGGTTTTTGCCCTCATCGCCATTATCCCCACAAATGCCGACAAA ATTTGCTTGGGCCACCACGCCGTGTCCAATGGTACAAAAGTCAATACACTGACCGAGAGG GGAGTGGAGGTGGTGAATGCCACAGAAACCGTTGAAAGAACGAATATTCCTAGAATTTGT TCTAAAGGGAAAAGAACCGTTGATCTCGGGCAATGCGGTCTGTTAGGCACAATCACAGGC CCTCCCCAGTGTGATCAATTTCTTGAGTTCAGTGCGGATCTTATCATTGAGAGACGGGAA GGGTCTGATGTCTGTTACCCCGGCAAGTTTGTGAACGAGGAAGCCCTGCGCCAGATCCTC AGAGAATCTGGGGGTATCGATAAGGAAGCTATGGGGTTTACTTATTCCGGGATCAGGACT AATGGGGCCACCAGCGCCTGCCGGCGGTCCGGCAGCTCATTCTACGCCGAGATGAAGTGG CTGCTGTCCAATACCGACAATGCGGCCTTTCCGCAGATGACCAAGAGCTATAAAAACACG CGCAAATCACCCGCTTTAATCGTCTGGGGGATACATCATTCAGTGAGCACTGCCGAGCAA ACCAAGCTGTATGGGAGCGGCAGTAAATTGGTTACTGTAGGTAGCTCTAACTACCAGCAG TCTTTCGTCCCAAGCCCAGGAGCCCGTCCGCAGGTGAATGGACTCAGTGGAAGGATTGAT TTTCATTGGCTAATGCTCAACCCGAACGATACTGTGACGTTTTCATTTAATGGCGCATTT ATCGCGCCCGATCGAGCCAGCTTCCTCCGGGGTAAGAGTATGGGGATCCAATCAGGAGTG CAGGTCGATGCTAACTGCGAGGGAGACTGTTACCATTCCGGCGGCACTATTATCAGCAAT CTGCCCTTCCAGAATATCGACTCCAGAGCCGTGGGAAAGTGTCCAAGGTACGTGAAACAG AGGAGCTTACTGCTTGCCACAGGGATGAAGAATGTCCCCGAGATTCCCAAAGGAAGGGGG CTGTTCGGAGCCATCGCAGGGTTCATTGAGAACGGGTGGGAAGGCTTAATCGATGGCTGG TACGGCTTCAGACACCAAAATGCACAGGGCGAAGGAACCGCCGCCGATTACAAGTCAACG CAATCCGCTATAGATCAGATAACCGGAAAGCTGAACAGACTCATCGAAAAAACAAACCAA CAGTTCGAACTTATAGACAACGAATTCAACGAGGTGGAAAAACAGATCGGGAACGTTATC AATTGGACACGAGACTCAATCACAGAGGTATGGTCCTACAACGCTGAACTCCTGGTTGCG ATGGAGAATCAGCACACCATTGACTTAGCCGACTCTGAGATGGATAAACTGTACGAGAGA GTGAAAAGGCAGCTCCGAGAGAACGCAGAAGAGGATGGTACAGGATGCTTCGAAATCTTT CACAAATGCGACGATGATTGTATGGCCAGCATCAGAAATAATACATATGACCATTCCAAA TATCGGGAAGAAGCAATGCAAAACCGGATCCAGATCGATCCTGTTAAACTCAGCAGCGGT TACAAGGACGTGATTCTGTGGTTCTCCTTCGGCGCATCATGTTTTATTCTTCTTGCTATT GTGATGGGACTAGTATTTATATGCGTGAAGAATGGCAACATGAGATGTACCATTTGCATC 511 ATGAATACCCAAATCCTTGTATTCGCTCTGATCGCAATCATTCCAACCAATGCTGATAAA ATCTGCTTAGGACACCACGCTGTGAGCAATGGTACAAAGGTCAATACACTGACAGAGCGG GGCGTAGAAGTGGTCAACGCCACCGAGACGGTGGAAAGGACCAATATCCCTAGGATTTGC TCGAAGGGCAAGAGAACAGTAGACCTGGGGCAATGTGGATTGTTGGGGACTATTACGGGA CCGCCCCAGTGTGATCAGTTTCTGGAGTTCAGCGCTGATCTCATCATCGAGCGCCGAGAG GGATCCGACGTGTGCTACCCAGGAAAATTCGTTAACGAGGAAGCATTAAGACAGATTTTA CGTGAATCGGGTGGCATTGATAAAGAAGCCATGGGGTTTACTTACAGTGGAATTAGAACC AATGGAGCCACCTCGGCTTGCCGGAGATCTGGGTCTAGCTTTTACGCAGAAATGAAGTGG CTGCTGTCTAACACGGATAATGCCGCGTTCCCGCAGATGACCAAAAGTTATAAAAATACC AGAAAGAGCCCTGCATTAATTGTCTGGGGCATTCACCACTCTGTTTCCACGGCCGAACAG ACAAAATTGTATGGAAGCGGAAACAAGCTGGTCACAGTCGGATCTAGCAACTACCAGCAG AGCTTTGTGCCCAGTCCAGGGGCCCGCCCTCAGGTCAATGGGCTTTCTGGGAGAATTGAT TTTCACTGGCTGATGTTGAACCCCAACGACACTGTGACCTTTAGCTTCAATGGCGCGTTT ATTGCGCCCGACAGAGCCTCCTTTTTACGGGGGAAAAGCATGGGAATACAATCTGGTGTG CAGGTGGATGCAAATTGCGAAGGAGACTGCTATCACTCCGGGGGTACCATTATTAGCAAT CTCCCATTCCAGAACATCGACTCCAGAGCCGTTGGTAAATGCCCCAGGTATGTCAAGCAG CGTAGTCTCTTGTTGGCCACAGGAATGAAAAACGTGCCTGAGATCCCCAAAGGGCGCGGC CTATTTGGGGCAATTGCCGGCTTTATCGAGAACGGATGGGAGGGCCTGATCGACGGTTGG TATGGCTTTCGCCATCAGAATGCTCAGGGGGAAGGCACAGCTGCAGACTACAAGAGCACC CAGAGCGCCATCGATCAAATCACCGGCAAGCTCAACCGGATCATCGAGAAGACAAATCAG CAATTTGAATTAATCGACAACGAGTTCAATGAGGTAGAAAAGCAGATAGGAAACGTGATC AACTGGACCAGGGATAGCATTACTGAAGTCTGGTCATACAATGCCGAACTCCTGGTGGCA ATGGAGAACCAGCACACTATTGATCTTGCCGACTCTGAGATGGACAAACTGTACGAGCGC GTGAAGCGACAGCTGAGGGAAAACGCTGAGGAAGACGGTACTGGCTGCTTTGAAATCTTC CACAAATGCGACGACGATTGCATGGCATCCATACGGAACAACACTTATGATCACTCAAAG TATCGGGAGGAAGCAATGCAGAATAGAATTCAAATCGATCCCGTTAAACTGAGCTCCGGC TACAAGGATGTGATTCTCTGGTTTAGCTTCGGAGCATCATGCTTTATCCTCCTAGCAATT GTAATGGGTCTGGTGTTCATATGCGTAAAGAATGGCAATATGCGCTGTACTATCTGTATT 512 ATGAACACGCAAATTCTAGTGTTTGCTCTAATTGCCATCATACCCACAAACGCCGATAAA ATCTGCCTTGGGCATCACGCAGTAAGTAACGGTACCAAGGTGAACACGCTCACAGAGCGC GGGGTCGAGGTCGTGAATGCCACCGAAACAGTGGAACGCACTAACATCCCTCGAATCTGT TCAAAAGGTAAGCGGACTGTGGATCTGGGACAGTGTGGCCTGCTTGGTACGATCACCGGT CCTCCCCAATGCGATCAGTTCCTGGAGTTCTCAGCAGACTTAATCATCGAGCGCAGAGAG GGTAGCGATGTCTGTTACCCCGGAAAGTTTGTGAAGGAAGAAGCCCTTCGCCAGATTCTC AGAGAGTCAGGAGGCATTGATAAGGAAGCCATGGGGTTTACCTACAGCGGTATCCGTACC AACGGAGCCACCTCTGCCTGCCGACGCTCAGGTTCTAGCTTCTACGCTGAAATGAAATGG TTACTGAGCAATACCGATAACGCCGCATTCCCCCAGATGACAAAAAGCTACAAGAATACC CGCAAAAGCCCTGCCCTTATAGTTTGGGGGATACATCACTCCGTGTCCACCGCAGAACAG ACCAAGCTGTACGGCAGCGGCAACAAATTGGTGACCGTGGGGAGTAGTAATTATCAACAG AGCTTTGTGCCCTCGCCTGGGGCCAGACCTCAGGTCAATGGACTTAGTGGAAGGATTGAT TTCCACTGGCTTATGCTCAATCCTAATGATACCGTCACATTCAGCTTCAACGGGGCGTTC ATCGCACCCGATCGCGCAAGCTTCCTGCGTGGGAAGAGTATGGGCATCCAATCTGGGGTT CAAGTGGATGCAAATTGTGAGGGCGATTGTTACCACAGCGGCGGGACGATCATCTCCAAC CTCCCCTTCCAGAATATTGATTCTCGTGCCGTTGGGAAATGTCCTAGATATGTGAAGCAG CGTTCCCTCCTGCTGGCTACAGGCATGAAGAACGTTCCGGAAATCCCCAAGGGCAGAGGA CTGTTTGGCGCCATTGCAGGATTTATTGAGAATGGATGGGAGGGCCTCATCGATGGTTGG TACGGATTCAGACACCAGAACGCTCAGGGGGAAGGAACAGCCGCCGATTATAAGTCTACC CAGTCGGCTATCGACCAAATCACCGGAAAACTGAACAGGCTGATAGAGAAAACTAACCAG CAGTTCGAGTTGATCGACAACGAGTTCAACGAAGTGGAGAAACAGATCGGCAACGTCATT AACTGGACACGCGACTCAATTACAGAGGTGTGGTCCTACAACGCTGAGCTGCTGGTAGCA ATGGAGAACCAGCATACCATCGACCTGGCTGATTCTGAAATGGATAAGCTGTATGAACGG GTCAAGCGTCAACTGCGCGAAAACGCCGAAGAGGATGGAACAGGCTGCTTCGAAATTTTT CATAAATGCGATGACGACTGCATGGCAAGCATCCGGAACAACACATACGATCACTCAAAA TACCGCGAGGAGGCTATGCAGAATCGCATTCAGATTGATCCTGTGAAGTTATCCTCCGGC TACAAAGATGTCATCCTCTGGTTCAGTTTCGGCGCGTCTTGCTTCATCCTCCTAGCAATC GTGATGGGTCTCGTTTTCATCTGTGTGAAGAACGGGAATATGAGATGCACTATTTGCATA 513 ATGAATACCCAGATCCTTGTGTTTGCTCTGATCGCCATCATTCCCACAAACGCCGACAAA ATTTGCCTCGGTCACCATGCTGTGTCAAACGGTACTAAAGTCAACACATTGACAGAGAGG GGCGTGGAGGTGGTGAATGCAACCGAGACCGTTGAGCGAACAAATATCCCTCGCATCTGC TCCAAGGGCAAGAAAACTGTGGATTTGGGCCAATGTGGGCTTTTGGGAACCATTACTGGG CCTCCTCAGTGTGATCAGTTCCTCGAGTTCTCTGCCGACCTGATTATTGAACGCCGAGAA GGTAGCGATGTCTGTTACCCAGGCAAATTCGTCAACGAAGAGGCACTTCGCCAGATACTG AGAGAGAGTGGAGGCATTGATAAAGAAGCTATGGGGTTTACCTATTCTGGGATAAGGACC AACGGGGCCACCAGTGCTTGTAGACGTAGTGGCAGCAGCTTCTACGCGGAAATGAAATGG CTCCTGTCAAATACAGACAATGCTGCTTTTCCTCAGATGACTAAATCGTACAAAAACACG CGGAAGAGCCCCGCCTTAATCGTGTGGGGAATCCACCACTCCGTGTCCACAGCGGAACAG ACCAAACTTTACGGCTCCGGGAATAAGCTAGTGACCGTGGGCAGCTCCAACTATCAACAA AGTTTCGTCCCTTCCCCCGGTGCGAGACCGCAGGTCAACGGACAGTCAGGGAGGATCGAT TTCCACTGGCTGATGTTAAACCCTAATGACACTGTGACTTTCTCCTTCAATGGAGCGTTC ATTGCACCGGATCGAGCGTCTTTTCTCCGGGGAAAGTCTATGGGTATCCAGTCTGGCGTG CAGGTGGATGCCAATTGCGAGGGAGATTGCTACCACTCCGGGGGCACTATCATCTCGAAT CTCCCCTTCCAGAACATCGACAGCCGGGCCGTGGGTAAATGCCCACGGTATGTCAAGCAA AGATCCTTACTGCTCGCCACAGGGATGAAGAACGTGCCTGAGATCCCTAAGGGCCGGGGG CTGTTTGGAGCCATCGCTGGGTTCATTGAAAACGGTTGGGAAGGCCTCATTGACGGATGG TATGGCTTCAGGCACCAGAACGCTCAGGGGGAGGGGACCGCCGCCGACTACAAGAGTACG CAATCTGCTATAGATCAGATCACTGGTAAACTCAACCGCTTGATCGAGAAAACCAATCAG CAGTTCGAGCTTATTGACAACGAGTTTAACGAGGTAGAGAAGCAGATTGGAAATGTCATC AATTGGACTAGAGACTCTATCACAGAGGTGTGGAGCTATAATGCCGAATTGTTGGTGGCA ATGGAAAACCAGCACACCATCGACCTGGCCGACAGCGAAATGGACAAGTTGTATGAACGC GTTAAACGTCAGTTGAGGGAGAACGCCGAGGAGGACGGGACGGGTTGCTTTGAAATCTTT CATAAGTGCGATGACGACTGTATGGCTTCTATCCGCAATAACACTTATGACCACAGTAAG TACCGGGAAGAAGCTATGCAAAACAGAATACAGATCGACCCAGTTAAATTATCAAGTGGC TATAAAGATGTGATCCTCTGGTTCAGCTTTGGAGCCTCCTGTTTCATTTTATTGGCCATA GTCATGGGCCTCGTATTTATCTGCGTGAAAAATGGCAACATGCGCTGCACCATCTGCATT 514 ATGAACACTCAGATCCTAGTGTTTGCTCTGATAGCGATCATACCCACCAATGCAGACAAA ATCTGTCTGGGCCATCATGCAGTCTCTAATGGAACCAAAGTGAACACCCTAACTGAGAGG GGCGTCGAGGTGGTGAATGCGACCGAAACTGTTGAAAGGACCAATATTCCCAGAATCTGC TCAAAGGGAAAAAAAACGGTGGACCTGGGGCAGTGTGGATTACTAGGCACGATCACCGGG CCTCCTCAGTGTGATCAATTTCTGGAGTTCAGCGCAGATCTTATTATTGAGAGAAGAGAG GGCTCTGACGTGTGCTACCCAGGCAAGTTCGTGAACGAGGAGGCTCTGCGGCAGATCCTA CGTGAGAGCGGAGGCATAGACAAGGAGGCAATGGGATTTACCTATAGCGGGATACGGACA AATGGCGCAACGTCCGCATGTCGCCGGAGTGGGTCTTCCTTTTACGCGGAGATGAAGTGG CTGCTGAGCAACACCGACAATGCCGCGTTTCCTCAGATGACAAAATCATATAAGAACACC CGAAAGTCCCCAGCACTCATTGTTTGGGGGATCCACCACAGTGTAAGCACCGCCGAGCAG ACTAAACTATACGGCAGCGGAAATAAACTTGTCACCGTCGGCTCCTCCAATTACCAACAG TCCTTCGTCCCTTCACCGGGTGCCAGGCCCCAGGTGAACGGACAATCCGGGCGTATTGAC TTTCACTGGCTGATGTTGAATCCAAACGACACCGTGACGTTTTCGTTCAACGGCGCATTT ATTGCCCCCGATCGGGCGAGCTTCCTGCGGGGAAAATCCATGGGCATCCAGAGTGGGGTC CAAGTGGACGCAAACTGTGAGGGCGACTGCTACCACTCCGGTGGAACAATCATTAGCAAT CTTCCCTTTCAGAACATTGACTCTCGGGCCGTAGGCAAGTGTCCGCGCTACGTGAAACAG CGCTCTCTGCTATTGGCTACAGGCATGAAGAATGTACCAGAGATACCTAAGGGACGAGGC CTCTTTGGGGCCATCGCCGGCTTCATCGAGAATGGGTGGGAAGGCCTGATTGACGGTTGG TATGGCTTTCGCCACCAGAATGCACAGGGTGAGGGAACGGCAGCCGATTACAAGTCCACG CAGAGTGCCATCGATCAGATTACCGGTAAATTAAACCGGCTCATTGAGAAAACTAACCAG CAGTTCGAACTGATCGATAATGAGTTTAATGAGGTGGAGAAGCAAATTGGCAACGTGATT AATTGGACCAGGGACAGTATAACGGAAGTGTGGTCCTATAATGCAGAATTGCTGGTGGCC ATGGAAAACCAGCACACGATCGATCTAGCTGATTCTGAGATGGACAAACTGTATGAGCGT GTTAAGCGACAGCTTCGCGAAAATGCAGAGGAAGATGGCACAGGCTGCTTTGAGATATTC CACAAATGCGACGATGACTGTATGGCTTCAATACGTAATAATACATACGACCACTCAAAA TACCGTGAAGAGGCCATGCAAAATCGCATCCAGATCGATCCTGTGAAACTATCATCAGGC TATAAAGACGTAATTCTTTGGTTTTCTTTCGGCGCAAGTTGCTTCATTCTTCTCGCCATT GTGATGGGACTTGTCTTCATATGTGTGAAAAACGGAAATATGCGCTGCACCATCTGTATC 515 ATGAACACTCAAATTCTAGTCTTCGCCCTGATCGCAATCATCCCTACTAATGCCGACAAG ATCTGTCTGGGACACCACGCAGTTTCAAACGGGACAAAGGTGAACACCCTGACCGAGCGG GGGGTAGAAGTGGTTAACGCAACTGAGACCGTGGAACGTACCAATATACCCAGGATATGT AGCAAGGGTAAAAAGACTGTCGATCTCGGTCAGTGTGGACTCCTGGGAACCATCACCGGA CCTCCCCAGTGTGATCAGTTCCTGGAGTTCAGCGCAGATTTAATCATCGAACGTCGCGAA GGATCCGACGTCTGCTATCCGGGTAAGTTTGTAAACGAGGAGGCTCTGAGACAAATCCTC AGAGAAAGTGGGGGCATAGACAAGGAGGCAATGGGGTTCACTTATTCTGGGATTAGGACA AATGGCGCCACTAGCGCTTGCCGCCGAAGTGGCAGTTCCTTCTACGCCGAGATGAAGTGG TTGCTTAGCAATACTGATAATGCTGCTTTCCCCCAGATGACGAAGTCTTACAAAAATACT CGTAAGAGCCCCGCGCTGATCGTGTGGGGGATCCACCACAGTGTGAGCACTGCCGAGCAA ACCAAGCTGTATGGGTCTGGGAATAAATTAGTGACCGTGGGCTCTAGTAACTACCAGCAG TCATTCGTTCCAAGTCCCGGCGCACGGCCTCAGGTTAATGGCCAGTCTGGCCGGATTGAC TTTCATTGGCTCATGCTGAATCCCAATGACACGGTGACATTCTCCTTTAACGGAGCATTT ATCGCACCAGACAGGGCTTCCTTCCTTCGCGGAAAATCCATGGGAATTCAGAGCGGGGTC CAGGTCGATGCTAATTGTGAAGGGGATTGTTACCACTCTGGAGGCACAATTATTAGCAAT CTGCCCTTCCAAAACATCGACTCCCGTGCTGTGGGCAAATGTCCACGCTACGTCAAGCAG AGATCATTACTTCTTGCTACAGGTATGAAAAACGTGCCGGAAATCCCTAAGGGGAGAGGA CTTTTCGGTGCCATAGCTGGATTCATAGAGAACGGATGGGAAGGGCTCATTGACGGCTGG TATGGCTTCAGACATCAGAACGCTCAGGGAGAGGGAACTGCTGCTGACTACAAGAGTACC CAGTCAGCTATCGACCAGATTACTGGGAAATTGAACCGCCTGATTGAAAAGACTAACCAG CAGTTCGAGCTCATCGACAATGAATTCAATGAAGTGGAGAAGCAGATCGGTAATGTCATC AATTGGACTCGGGATTCAATTACAGAGGTGTGGTCTTACAATGCAGAGCTGCTGGTTGCC ATGGAAAACCAGCATACCATTGACCTGGCAGACAGTGAAATGGATAAACTGTACGAGAGG GTTAAACGGCAATTGCGCGAAAATGCCGAGGAAGACGGGACAGGATGTTTTGAGATCTTT CATAAATGCGATGACGACTGTATGGCTTCGATTCGAAACAATACTTACGACCACTCAAAG TATAGAGAAGAAGCAATGCAGAACCGGATTCAAATCGACCCTGTTAAGCTGTCATCCGGC TATAAGGATGTAATTCTCTGGTTCAGCTTTGGTGCATCATGTTTTATACTCCTCGCCATC GTGATGGGCCTTGTATTCATCTGCGTCAAGAACGGGAATATGAGATGCACCATTTGTATT 516 ATGAACACACAGATCCTCGTTTTTGCCTTGATCGCAATCATCCCAACAAACGCAGACAAA ATCTGTCTGGGTCACCACGCCGTCAGTAACGGGACTAAGGTGAACACCCTCACGGAGCGG GGAGTCGAGGTCGTGAATGCTACTGAGACCGTGGAGCGTACCAACATCCCCAGGATTTGC AGCAAAGGAAAGCGGACCGTAGACCTCGGGCAATGTGGGCTGTTAGGCACAATCACTGGC CCTCCCCAGTGTGACCAGTTTCTTGAGTTCTCTGCTGACTTAATCATCGAGCGTCGAGAA GGGTCAGATGTCTGCTATCCTGGCAAATTTGTGAATGAGGAAGCACTTCGGCAGATTTTG AGAGAATCGGGCGGCATCGATAAGGAGGCTATGGGCTTCACCTACTCTGGGATTAGGACC AATGGGGCCACCAGTGCCTGTAGGCGCTCAGGCAGTTCCTTTTACGCTGAGATGAAGTGG CTACTGAGTAATACGGATAACGCCGCCTTCCCTCAGATGACTAAGAGCTACAAGAACACC AGAAAATCTCCTGCCTTGATAGTGTGGGGAATACACCACAGCGTATCCACCGCAGAACAA ACCAAGTTGTATGGGAGCGGAAACAAGTTGGTCACCGTTGGATCATCGAATTACCAGCAG AGCTTTGTGCCTTCTCCCGGCGCTCGGCCCCAGGTGAACGGGCTGAGTGGTCGTATCGAC TTCCATTGGCTTATGCTTAACCCGAATGACACCGTAACGTTCAGCTTCAATGGCGCTTTT ATTGCACCCGACCGCGCGTCATTCCTACGCGGAAAGTCCATGGGGATCCAGTCTGGTGTG CAGGTGGACGCCAATTGTGAGGGCGATTGCTATCACTCCGGAGGGACAATTATCTCGAAT CTCCCGTTCCAGAACATTGACAGCCGGGCTGTCGGGAAGTGCCCGCGCTATGTGAAACAG AGGTCCCTCCTTCTTGCAACTGGCATGAAAAACGTTCCCGAGATCCCAAAGGGCCGTGGA CTGTTTGGAGCCATCGCTGGCTTCATAGAGAACGGCTGGGAGGGCCTGATTAATGGTTGG TACGGCTTTAGACACCAAAATGCCCAGGGAGAAGGCACCGCCGCAGACTACAAATCGACT CAGTCCGCAATTGATCAGATTACCGGGAAACTCAACCGGCTCATCGAAAAGACTAACCAG CAGTTTGAATTGATTGACAACGAGTTCAATGAGGTGGAGAAGCAGATCGGGAATGTCATC AACTGGACACGGGACTCAATAACCGAAGTGTGGTCATACAATGCGGAGCTGCTTGTCGCC ATGGAAAATCAGCACACAATCGACCTAGCAGACTCTGAAATGGACAAGCTGTATGAGAGA GTGAAGCGACAATTACGTGAAAATGCGGAGGAGGACGGAACTGGCTGCTTCGAGATCTTC CACAAGTGTGATGACGATTGCATGGCCTCTATCCGCAACAACACTTACGATCATAGCAAA TACAGGGAGGAAGCCATGCAGAACCGGATCCAGATTGATCCTGTGAAGCTGTCTAGTGGC TATAAAGACGTAATCCTCTGGTTCAGCTTCGGCGCAAGCTGCTTCATCCTTCTCGCCATA GTGATGGGCTTAGTGTTTATATGCGTGAAGAACGGGAACATGCGCTGTACCATTTGTATC 517 ATGAATACTCAAATCCTCGTCTTTGCACTCATAGCAATTATCCCTACCAACGCTGATAAG ATTTGTTTGGGGCATCACGCCGTCTCCAACGGGACTAAGGTAAATACATTGACGGAAAGA GGGGTGGAAGTTGTGAATGCCACTGAGACTGTGGAGCGGACCAACATCCCCCGTATATGT TCAAAAGGAAAACGCACAGTCGACTTGGGTCAGTGCGGACTCCTGGGGACTATTACCGGG CCACCTCAGTGCGACCAATTTCTGGAATTCAGCGCGGACCTGATCATTGAGCGCCGAGAG GGAAGTGACGTATGCTACCCTGGGAAGTTTGTTAATGAGGAAGCACTAAGGCAAATACTG CGGGAATCGGGCGGAATTGATAAGGAAGCTATGGGCTTCACGTACAGCGGAATTAGAACC AACGGGGCTACGAGTGCGTGTAGACGGTCCGGTAGTTCCTTTTACGCCGAAATGAAATGG CTCCTAAGCAATACGGACAACGCCGCATTTCCTCAGATCACAAAATCATACAAGAACACT AGGAAGAGTCCCGCCCTTATTGTGTGGGGAATTCATCACAGTGTGAGTACTGCCGAACAG ACTAAGCTCTATGGCTCAGGAAATAAGCTCGTCACCGTTGGGTCCAGTAACTATCAGCAG TCTTTTGTCCCGTCACCTGGGGCCAGACCTCAAGTCAACGGCTTGAGTGGACGTATCGAT TTTCATTGGCTGATGCTGAACCCAAATGACACTGTCACTTTTAGCTTCAATGGGGCTTTT ATCGCTCCAGATCGGGCATCCTTCCTGCGTGGGAAATCCATGGGAATTCAATCAGGTGTC CAGGTGGATGCTAATTGCGAGGGGGACTGCTATCACTCAGGGGGGACTATTATATCCAAT CTGCCCTTTCAGAACATCGATTCCAGGGCGGTGGGCAAATGTCCTAGATATGTAAAACAG AGGTCTCTGCTTCTGGCGACAGGCATGAAGAATGTTCCTGAAATCCCCAAGGGCAGGGGC CTGTTCGGGGCCATTGCAGGCTTTATCGAGAACGGCTGGGAGGGGCTAATCGACGGCTGG TACGGCTTTCGACATCAGAACGCTCAGGGTGAAGGCACGGCTGCCGATTATAAGTCGACG CAGTCAGCCATTGATCAAATCACTGGCAAACTTAATCGCCTCATAGAGAAGACCAATCAG CAGTTTGAACTCATCGATAACGAGTTCAACGAGGTGGAAAAACAAATTGGTAACGTCATC AATTGGACCAGGGACAGTATTACAGAGGTTTGGTCCTACAACGCCGAATTGTTGGTGGCA ATGGAAAATCAGCATACTATCGACCTGGCTGACAGCGAAATGGACAAGCTCTATGAACGG GTAAAGAGGCAGTTACGGGAGAACGCTGAGGAGGACGGCACTGGGTGTTTCGAGATCTTT CATAAATGCGATGATGACTGCATGGCTTCTATCCGTAATAACACGTATGATCACTCCAAG TATCGGGAAGAGGCCATGCAGAACCGGATCCAAATCGATCCCGTAAAGTTGTCATCCGGC TACAAAGACGTAATTTTGTGGTTTTCTTTCGGAGCTTCCTGTTTCATACTGCTAGCTATC GTAATGGGGTTGGTGTTCATCTGCGTGAAGAATGGAAACATGAGGTGTACCATCTGTATC 518 ATGAACACCCAGATCCTCGTCTTCGCTCTAATCGCCATAATCCCCACTAATGCCGACAAA ATTTGTCTCGGACACCACGCCGTTAGCAACGGGACAAAAGTTAACACACTTACTGAGAGA GGGGTCGAGGTTGTAAATGCTACAGAAACCGTGGAGAGGACTAATATTCCAAGAATTTGT TCAAAGGGAAAAAAGACAGTGGATCTTGGCCAGTGCGGGCTGCTGGGGACAATCACAGGA CCACCCCAGTGCGACCAATTTCTGGAATTCTCTGCAGACCTGATTATTGAACGCCGTGAG GGGAGTGACGTTTGCTATCCCGGGAAGTTTGTTAACGAAGAGGCTCTTAGACAAATCCTC CGCGAATCTGGGGGGATCGATAAAGAGGCCATGGGGTTTACCTACTCCGGCATTAGGACT AATGGAGCTACCTCCGCCTGTAGGAGGTCTGGAAGCTCATTTTACGCAGAAATGAAATGG TTGCTCAGCAACACCGACAATGCAGCGTTTCCGCAAATGACCAAGAGTTACAAGAACACC CGAAAGTCTCCTGCGTTGATTGTGTGGGGCATTCACCATTCAGTTTCCACTGCAGAGCAG ACAAAACTGTACGGTTCAGGAAACAAGCTGGTAACCGTGGGATCTTCCAACTATCAGCAG AGCTTCGTGCCCTCGCCCGGAGCCCGCCCTCAGGTGAACGGACAGAGTGGAAGGATCGAC TTCCACTGGCTGATGTTGAATCCCAACGATACCGTGACTTTCTCTTTCAACGGTGCATTT ATAGCCCCTGACCGCGCTTCCTTTCTCCGAGGAAAAAGCATGGGCATCCAGTCTGGAGTG CAGGTTGACGCAAATTGCGAAGGCGACTGTTACCATAGTGGCGGCACAATAATTTCTAAC CTTCCCTTTCAAAATATTGACAGCCGCGCAGTAGGTAAGTGTCCTAGATACGTGAAGCAG AGGAGCCTACTGCTCGCCACTGGCATGAAAAATGTGCCGGAGATCCCTAAGGGCAGAGGG CTGTTCGGCGCCATCGCCGGCTTCATCGAAAATGGATGGGAGGGGTTGATAGACGGTTGG TACGGCTTCCGGCATCAGAACGCCCAGGGTGAGGGGACCGCCGCTGATTATAAAAGTACC CAGTCTGCTATCGATCAGATCACCGGGAAGCTCAACCGTCTTATTGAGAAGACCAATCAG CAATTCGAACTCATCGACAACGAGTTTAACGAGGTTGAAAAGCAAATTGGAAATGTGATT AATTGGACACGGGATTCAATAACCGAAGTCTGGTCGTACAACGCAGAGCTACTTGTGGCA ATGGAGAACCAGCACACCATAGACCTTGCCGACTCCGAAATGGATAAGTTGTATGAAAGA GTGAAACGCCAGCTGCGGGAGAATGCCGAGGAAGATGGGACAGGATGTTTTGAGATCTTT CACAAGTGCGACGATGATTGCATGGCCTCCATTCGAAACAATACTTATGACCATAGCAAA TACAGAGAGGAGGCCATGCAGAACCGGATTCAAATCGATCCTGTTAAGTTATCTTCAGGT TACAAGGATGTCATCCTTTGGTTCTCGTTTGGAGCCAGCTGCTTCATATTGCTGGCTATC GTGATGGGTCTGGTGTTTATCTGCGTTAAGAACGGCAATATGAGATGTACGATCTGTATT 519 ATGAACACTCAGATTCTGGTCTTTGCCCTGATTGCTATCATCCCAACCAACGCAGACAAG ATCTGTCTGGGACACCATGCCGTATCTAACGGAACCAAGGTTAACACGTTGACCGAGCGC GGCGTTGAAGTCGTCAATGCCACTGAGACCGTGGAGCGAACAAACATTCCCAGAATCTGT AGCAAGGGCAAACGGACTGTGGACCTGGGCCAGTGTGGGTTGTTGGGAACAATCACAGGA CCTCCACAGTGTGATCAGTTCCTGGAGTTTAGTGCAGACCTTATCATCGAACGCAGAGAA GGTTCCGACGTCTGTTACCCTGGGAAATTTGTAAATGAGGAGGCCTTGAGACAGATCCTT AGGGAATCTGGAGGAATCGACAAGGAGGCCATGGGCTTTACCTATAGCGGAATAAGGACC AATGGCGCCACTTCCGCCTGTAGGAGAAGCGGTTCATCATTCTATGCAGAGATGAAGTGG TTGTTAAGTAACACGGATAATGCTGCGTTTCCACAGATGACCAAGTCCTACAAGAATACC CGAAAATCCCCCGCACTCATTGTCTGGGGAATACACCACAGCGTCTCAACAGCTGAGCAA ACAAAACTCTATGGATCCGGGAATAAGCTCGTGACCGTAGGCTCATCAAACTACCAGCAG TCGTTCGTGCCATCTCCAGGGGCCCGGCCTCAGGTCAACGGTCTGTCAGGACGCATTGAT TTTCACTGGCTGATGCTTAATCCCAACGATACCGTCACATTCTCCTTCAATGGGGCGTTT ATTGCGCCTGACAGAGCTAGCTTTTTGCGAGGTAAGTCTATGGGCATACAGTCTGGGGTG CAAGTGGACGCGAATTGCGAGGGGGACTGCTATCATTCCGGAGGCACCATCATCTCCAAC CTCCCATTTCAAAATATCGACAGTAGGGCGGTGGGGAAGTGCCCCCGTTACGTAAAACAG CGCTCCCTCCTGCTGGCCACAGGGATGAAGAATGTTCCAGAAATACCAAAAGGAAGGGGT CTGTTTGGTGCCATCGCAGGCTTCATCGAAAACGGATGGGAGGGGCTGATTGATGGTTGG TACGGATTTAGACACCAGAATGCCCAGGGCGAAGGAACTGCCGCTGATTATAAGAGCACA CAGTCAGCTATAGACCAGATCACTGGGAAGCTAAACAGAATCATTGAAAAGACGAACCAG CAGTTCGAACTAATCGACAATGAGTTCAACGAGGTGGAAAAGCAGATTGGGAACGTGATA AATTGGACACGCGACTCCATAACGGAAGTGTGGAGCTACAATGCGGAGCTGCTGGTGGCT ATGGAGAATCAGCACACCATCGACCTTGCGGATAGTGAAATGGATAAACTCTACGAGCGT GTTAAGCGGCAATTGCGGGAGAACGCCGAGGAGGATGGGACCGGGTGCTTCGAGATTTTC CACAAATGTGATGATGACTGTATGGCCTCCATACGCAATAATACCTACGACCATAGCAAA TATCGGGAGGAAGCCATGCAGAACCGAATCCAAATAGACCCAGTGAAGCTGAGTTCCGGC TATAAAGATGTGATTCTCTGGTTTAGCTTTGGAGCAAGCTGTTTTATCCTGTTAGCGATT GTGATGGGTTTAGTGTTCATTTGTGTGAAAAACGGTAACATGCGATGCACCATTTGTATC 520 ATGAATACCCAGATCCTTGTCTTTGCCCTGATAGCCATTATTCCCACCAACGCAGATAAA ATTTGCCTCGGGCACCACGCTGTGAGCAACGGCACAAAGGTGAATACTCTGACAGAACGG GGTGTAGAGGTGGTTAATGCAACAGAGACAGTGGAGCGCACAAACATCCCCAGAATCTGC TCTAAGGGCAAGCGGACTGTGGATTTAGGGCAATGTGGACTGCTAGGTACTATCACCGGG CCTCCACAGTGTGACCAGTTTTTGGAGTTCTCTGCCGATCTTATCATCGAGCGTCGAGAG GGGAGTGATGTGTGCTACCCAGGCAAATTTGTGAACGAGGAAGCCCTTCGGCAGATCCTG AGAGAGTCCGGCGGCATCGACAAAGAGGCCATGGGTTTTACCTATTCAGGAATCCGAACC AACGGAGCCACCTCCGCCTGTAGGCGGAGTGGGTCTAGCTTTTATGCAGAAATGAAATGG TTGCTGTCCAACACCGATAATGCAGCTTTCCCACAGATAACAAAGTCTTACAAAAATACG CGCAAGTCCCCAGCGCTAATTGTGTGGGGCATTCATCACAGCGTGTCTACTGCGGAGCAG ACCAAGCTGTACGGGAGCGGGAATAAATTGGTCACAGTCGGGAGCTCGAACTACCAGCAA AGCTTCGTTCCTAGCCCCGGGGCAAGGCCTCAGGTGAACGGACTGAGCGGCAGAATTGAC TTCCACTGGTTGATGCTTAATCCTAACGATACAGTGACCTTTAGCTTCAATGGAGCGTTC ATTGCCCCTGATCGCGCCTCCTTTCTCCGGGGGAAAAGTATGGGGATTCAATCCGGGGTG CAGGTTGACGCTAATTGTGAGGGTGATTGCTACCACTCCGGGGGCACCATTATAAGCAAT TTACCGTTTCAGAATATTGACTCTCGAGCCGTGGGGAAATGTCCCCGGTACGTCAAGCAA AGGTCTTTGCTGCTGGCTACCGGCATGAAAAACGTACCCGAGATCCCAAAAGGACGCGGC CTCTTCGGTGCAATCGCCGGCTTTATAGAGAATGGATGGGAAGGGCTTATTGACGGGTGG TATGGGTTCCGCCATCAGAATGCGCAAGGCGAAGGAACTGCCGCCGATTACAAGAGTACA CAGTCCGCCATCGATCAAATTACTGGCAAACTAAATAGACTCATCGAGAAGACAAACCAG CAGTTTGAACTCATTGACAACGAATTCAACGAGGTAGAGAAACAGATTGGCAACGTCATC AATTGGACACGGGACAGTATCACAGAAGTCTGGTCCTACAACGCAGAGCTTCTCGTTGCT ATGGAAAATCAGCACACCATTGACCTGGCTGACTCCGAGATGGACAAGTTGTATGAGCGT GTGAAAAGGCAGTTGCGTGAAAACGCCGAGGAAGACGGCACAGGTTGTTTTGAGATCTTT CACAAATGCGACGACGATTGTATGGCAAGCATAAGAAACAATACTTATGACCACAGTAAA TATCGAGAGGAAGCCATGCAGAACAGAATCCAAATCGACCCTGTGAAACTAAGCTCAGGC TACAAGGACGTGATCCTCTGGTTCTCCTTTGGTGCTTCCTGCTTTATTCTCCTTGCCATC GTCATGGGCCTCGTGTTCATCTGCGTTAAGAACGGTAATATGCGGTGTACTATTTGTATC 521 ATGAATACCCAGATTCTCGTTTTTGCCCTAATAGCTATCATTCCTACAAATGCCGATAAA ATTTGCTTGGGCCATCATGCCGTGAGCAACGGGACTAAGGTTAACACCCTGACTGAGCGG GGCGTAGAGGTGGTTAACGCCACAGAGACAGTGGAACGGACGAACATTCCAAGAATTTGT TCAAAGGGCAAGAAAACGGTGGACCTCGGGCAATGTGGTCTGCTAGGCACTATAACAGGA CCTCCTCAGTGCGATCAGTTTCTGGAATTCAGTGCAGATCTGATCATCGAGCGTCGAGAG GGATCAGATGTCTGTTATCCTGGGAAGTTCGTCAATGAGGAGGCACTGAGACAGATACTC AGAGAGAGCGGAGGCATTGATAAGGAAGCTATGGGTTTTACCTATTCTGGTATTAGAACT AACGGAGCCACAAGTGCCTGTCGTCGGTCGGGCTCTTCGTTTTACGCTGAGATGAAGTGG CTGCTGAGTAATACTGACAATGCAGCGTTCCCCCAGATGACTAAGAGTTATAAAAACACC CGTAAAAGCCCAGCACTGATCGTGTGGGGAATTCATCATTCAGTCTCTACAGCCGAGCAG ACCAAGCTCTACGGGTCTGGCAACAAGCTCGTTACAGTAGGATCTAGCAACTATCAACAG AGCTTTGTACCATCCCCTGGAGCTCGTCCACAAGTGAACGGTCAGTCGGGCCGTATCGAC TTTCACTGGCTGATGCTGAATCCTAATGACACGGTGACTTTCAGTTTCAATGGAGCCTTC ATCGCACCAGACCGCGCAAGCTTTCTACGCGGGAAGAGTATGGGGATTCAGTCCGGCGTT CAAGTGGACGCCAATTGCGAAGGGGACTGTTACCATAGCGGCGGCACCATCATTAGTAAC CTCCCATTTCAAAACATCGATTCTCGCGCCGTGGGGAAATGTCCTAGATACGTGAAACAG CGCAGCCTGCTCCTCGCAACTGGCATGAAGAATGTTCCAGAGATTCCGAAGGGGCGGGGT CTCTTTGGCGCCATCGCCGGGTTCATCGAAAACGGGTGGGAGGGACTGATCGATGGCTGG TATGGCTTCCGACATCAAAACGCACAGGGTGAGGGCACAGCTGCCGATTATAAATCCACG CAGAGCGCAATCGATCAGATCACCGGCAAACTGAACAGGCTGATCGAGAAAACTAATCAG CAGTTCGAGCTTATCGATAATGAATTCAATGAAGTGGAGAAGCAGATTGGGAATGTGATT AATTGGACTCGGGACTCTATTACTGAAGTGTGGAGTTACAACGCCGAGCTCTTGGTTGCT ATGGAGAATCAGCATACAATTGACTTGGCAGATTCCGAGATGGATAAGCTCTACGAGCGT GTCAAGCGGCAACTGAGAGAGAACGCCGAAGAGGATGGGACGGGGTGCTTCGAGATTTTC CATAAGTGCGACGATGATTGTATGGCCAGTATCAGAAATAATACATATGACCATAGCAAA TACAGAGAGGAAGCAATGCAGAACCGGATCCAGATTGATCCGGTGAAGCTCTCTAGCGGA TATAAGGATGTTATCCTGTGGTTTTCTTTTGGAGCCTCCTGTTTCATTCTGCTGGCCATT GTAATGGGACTAGTCTTCATATGTGTAAAAAACGGCAATATGAGGTGCACTATTTGTATT 522 ATGAACACACAGATCCTGGTATTCGCGCTCATCGCAATTATACCAACAAATGCCGATAAG ATATGCTTGGGACATCACGCCGTATCCAACGGTACCAAAGTGAATACACTGACCGAACGT GGCGTAGAGGTGGTGAACGCCACTGAGACGGTTGAGCGCACCAACATCCCCCGCATCTGC TCCAAGGGAAAACGCACCGTCGACCTGGGACAGTGTGGGCTGCTCGGCACAATCACGGGT CCTCCTCAGTGTGACCAATTCTTGGAGTTCAGCGCAGATCTAATTATAGAGAGGCGGGAG GGAAGCGATGTGTGCTATCCTGGCAAATTTGTCAACGAGGAAGCCCTTCGCCAGATTCTT CGGGAGTCCGGCGGAATCGATAAAGAGGCTATGGGGTTTACATATAGTGGAATCCGCACC AATGGCGCCACGTCGGCCTGTAGGAGGAGCGGATCCAGTTTCTATGCCGAGATGAAATGG CTCCTCAGTAATACTGATAATGCTGCGTTCCCCCAGATAACCAAATCGTACAAAAATACA CGGAAGTCTCCCGCGCTGATTGTATGGGGCATACACCACTCCGTATCGACTGCCGAACAG ACTAAGCTCTACGGCTCTGGGAACAAGTTAGTGACCGTCGGCTCGAGCAATTACCAGCAG AGTTTTGTCCCATCACCAGGGGCAAGACCTCAGGTGAACGGGCTTTCAGGGAGGATTGAC TTCCACTGGCTGATGCTGAACCCAAATGACACTGTCACCTTTTCGTTCAACGGGGCATTT ATCGCCCCAGACAGGGCCTCATTCCTTAGAGGCAAATCTATGGGCATTCAAAGCGGGGTT CAGGTGGACGCGAACTGTGAGGGCGACTGTTATCATAGCGGTGGCACTATTATCTCCAAC CTGCCCTTTCAGAATATAGACAGTAGAGCCGTGGGTAAGTGCCCACGGTATGTGAAGCAA AGGTCCCTGCTCCTCGCTACGGGGATGAAGAATGTGCCAGAGATTCCTAAGGGTCGCGGC CTGTTCGGAGCAATAGCGGGTTTTATAGAAAATGGTTGGGAAGGATTAATAGATGGGTGG TACGGGTTTAGGCACCAGAATGCTCAGGGAGAGGGTACGGCAGCTGATTATAAGTCTACA CAATCTGCCATCGACCAGATCACCGGAAAGCTCAACAGACTTATCGAAAAAACTAACCAG CAGTTCGAATTGATCGACAATGAATTTAATGAAGTGGAGAAGCAGATAGGTAACGTGATT AACTGGACTCGGGACTCAATCACTGAAGTTTGGAGTTACAACGCAGAGCTCCTGGTCGCC ATGGAGAACCAGCATACCATAGATCTCGCTGACAGTGAGATGGACAAACTGTACGAAAGA GTGAAGCGTCAGCTCAGAGAGAATGCGGAGGAAGATGGGACCGGATGCTTCGAAATTTTT CACAAGTGTGACGACGACTGTATGGCCAGCATAAGGAATAACACTTATGATCATTCTAAG TATCGTGAGGAGGCAATGCAGAACAGGATTCAAATTGATCCGGTTAAGCTTTCTTCAGGA TACAAGGACGTCATTCTGTGGTTCTCCTTCGGGGCATCTTGCTTTATTTTACTTGCAATC GTGATGGGGTTAGTCTTTATCTGCGTGAAAAATGGGAACATGAGGTGTACTATCTGCATC 523 ATGAATACACAGATCCTGGTCTTTGCTCTGATCGCAATTATTCCTACGAATGCAGACAAG ATTTGCCTTGGACACCACGCCGTATCTAACGGCACCAAAGTCAATACCCTGACCGAGCGG GGCGTTGAAGTTGTTAATGCCACCGAAACAGTAGAACGCACTAATATACCACGCATTTGC TCGAAAGGGAAAAAGACCGTTGACCTCGGCCAGTGCGGCCTGCTTGGCACAATCACAGGA CCACCACAGTGTGACCAATTTCTCGAATTTTCCGCTGATCTGATAATAGAGAGGCGGGAA GGGAGCGACGTGTGTTATCCAGGGAAGTTCGTTAACGAGGAAGCACTTAGGCAAATACTG CGGGAAAGCGGTGGCATCGATAAAGAGGCCATGGGCTTTACCTACAGTGGTATTAGGACA AACGGCGCGACATCCGCGTGTAGGAGAAGCGGCTCATCCTTCTACGCTGAAATGAAGTGG CTGTTAAGTAATACCGATAATGCGGCTTTCCCGCAAATGACTAAGAGTTACAAAAACACT AGAAAGTCTCCAGCTCTGATTGTTTGGGGGATTCATCATTCTGTGAGTACAGCCGAACAG ACCAAGTTGTACGGCTCCGGAAACAAGCTGGTGACTGTAGGCTCTTCTAATTATCAACAG TCTTTTGTACCTAGTCCGGGTGCCCGCCCACAGGTAAACGGGCAGTCAGGCAGAATCGAT TTCCACTGGCTCATGCTGAATCCAAACGATACCGTCACCTTCAGTTTCAATGGAGCATTT ATAGCACCGGACCGCGCGTCATTCCTACGGGGTAAATCCATGGGCATTCAGAGCGGGGTT CAAGTAGATGCCAACTGTGAGGGCGACTGCTATCACTCTGGCGGTACGATCATAAGCAAC CTTCCGTTTCAAAATATCGACAGCCGTGCTGTTGGCAAATGCCCCCGTTACGTGAAGCAG AGAAGCCTTCTGTTGGCTACTGGAATGAAGAATGTGCCCGAGATTCCTAAGGGAAGAGGC CTCTTCGGAGCGATCGCTGGATTTATAGAAAATGGCTGGGAAGGACTAATCGACGGCTGG TATGGGTTTAGACACCAGAACGCACAGGGGGAGGGCACTGCTGCGGATTATAAGTCGACA CAGTCCGCGATCGACCAGATCACCGGTAAACTCAATCGGCTCATTGAGAAGACAAACCAA CAGTTCGAGTTGATCGATAATGAATTTAATGAAGTGGAAAAGCAGATAGGAAATGTGATC AACTGGACACGGGACAGCATTACCGAAGTATGGAGTTACAATGCAGAGCTGCTGGTTGCT ATGGAGAACCAGCACACGATTGATTTGGCCGATTCGGAAATGGACAAGCTTTACGAGCGG GTGAAAAGGCAACTCCGCGAAAATGCTGAAGAGGATGGGACTGGCTGTTTCGAGATTTTT CACAAGTGCGACGACGATTGCATGGCCAGCATAAGGAATAATACATATGACCACTCCAAA TACAGGGAAGAAGCAATGCAGAACAGAATCCAGATCGACCCTGTGAAGTTGAGTAGTGGA TACAAGGATGTCATCCTGTGGTTTTCTTTTGGCGCCTCATGCTTCATTCTGCTGGCAATT GTAATGGGCCTGGTGTTCATTTGTGTGAAAAACGGAAATATGAGGTGTACAATCTGTATC 524 ATGAACACGCAAATTTTGGTCTTCGCATTGATTGCAATTATTCCTACGAACGCAGACAAG ATCTGTCTAGGACACCACGCTGTGTCAAACGGAACAAAAGTGAACACGCTGACCGAGCGG GGGGTCGAAGTGGTGAATGCAACTGAAACTGTAGAACGAACTAACATCCCAAGAATTTGT AGCAAAGGAAAGAAGACAGTTGACCTGGGTCAGTGCGGACTGCTCGGTACCATCACCGGT CCGCCGCAGTGCGACCAATTTTTAGAGTTCTCTGCAGACTTAATCATCGAGCGCAGAGAG GGCTCAGATGTCTGCTACCCCGGTAAGTTCGTGAACGAGGAGGCGCTTCGTCAGATTCTG CGAAAGAGTGGCGGGATCGACAAGGAGGCTATGGGCTTCACTTACTCAGGCATTCGTACG AATGGCGCCACATCCACCTGCAGGCGGAGCGGGTCTAGTTTTTACGCCGAGATGAAGTGG TTGTTATCGAACACCGACAATGCGGCCTTCCCCCAGATGACAAAATCATACAAAAATACG CGCAAGTCACCCGCTATAATTGTGTGGGGCATTCACCACAGCGTCTCTACGGCCGAACAG ACGAAATTATACGGGTCTGGGAACAAACTGGTGACAGTCGGCAGCAGTAACTACCAGCAA TCTTTCGTGCCATCGCCAGGAGCCCGCCCGCAGGTCAATGGGTTATCTGGACGGATAGAC TTCCATTGGCTGATGCTTAACCCAAACGACACTGTTACCTTTAGCTTCAATGGGGCTTTT ATCGCGCCTGATAGAGCTTGCTTCCTGAGAGGAAAGTCAATGGGAATCCAGTCAGGTGTG CAGGTGGACGCGGATTGTGAAGGTGATTGCTACCACAGTGGGGGGACAATCATTAGTAAT CTGCCATTCCAGAATATTGATTCACGTGCAGTAGGAAAATGTCCACGATATGTTAAGCAA AGGTCGTTGCTACTCGCTACTGGTATGAAAAACGTACCAGAAATACCTAAGGGAAGGGGA CTATTTGGTGCAATTGCAGGGTTCATCGAGAACGGCTGGGAGGGCCTCATAGACGGATGG TATGGTTTCCGGCACCAGAACGCACAGGGCGAAGGCACAGCAGCCGATTACAAGTCCACA CAGAGCGCAATCGACCAGATCACAGGCAAACTCAATAGGCTCATAGAAAAGACCAATCAG CAGTTTGAGCTCATTGACAACGAATTCAATGAAGTGGAGCGGCAGATAGGAAACGTGATA AATTGGACCCGGGATAGCATTACGGAGGTCTGGTCCTATAACGCGGAGCTGCTGGTGGCC ATGGAGAATCAGCACACCATTGACCTGGCCGATAGCGAAATGGATAAGCTGTATGAGCGC GTGAAGAGGCAGCTGCGGGAGAACGCTGAAGAGGACGGCACGGGCTGTTTTGAGATTTTC CACAAGTGTGATGACGACTGCATGGCCTCCATCCGAAACAACACCTATGACCATTCCAAA TACCGGGAAGAGGCAATGCAAAATAGAATACAGATCGATCCTGTGAAGCTGTCCAGCGGC TATAAAGACGTTATTCTGTGGTTCTCTTTCGGGGCATCCTGTTTTATACTCTTAGCTATC GTTATGGGCCTGGTCTTTATTTGCGTGAAGAACGGCAACATGCGGTGCACGATTTGCATC 525 ATGAACACCCAGATCCTGGTTTTCGCTTTAATCGCGATTATACCCACAAACGCTGATAAG ATCTGCCTTGGGCATCATGCCGTGAGTAATGGTACAAAGGTCAATACACTCACTGAGAGA GGCGTCGAGGTCGTGAATGCTACTGAAACCGTCGAGAGAACAAATATACCCAGGATTTGC AGTAAAGGCAAGAAAACAGTAGATCTCGGTCAGTGCGGGTTGCTCGGGACCATCACTGGG CCACCTCAGTGCGACCAATTCTTGGAGTTTTCCGCCGACCTCATTATTGAGCGCCGGGAA GGCAGTGACGTCTGTTACCCCGGGAAATTCGTTAATGAGGAGGCCCTGAGACAGATCCTC CGGGAGAGCGGGGGAATTGACAAGGAGGCCATGGGGTTCACCTATTCTGGAATTAGGACT AACGGCGCCACATCCGCGTGTCGCCGGTCTGGGTCATCTTTCTACGCCGAGATGAAATGG TTGCTCAGCAATACCGATAACGCCGCCTTTCCTCAGATGACCAAGTCATACAAAAACACA CGAAAGTCACCCGCACTGATAGTGTGGGGCATACACCACAGCGTTTCAACTGCCGAACAG ACAAAATTGTACGGATCTGGCAATAAGCTGGTCACCGTGGGCTCCAGTAACTACCAGCAA AGCTTCGTCCCCTCCCCCGGTGCTAGGCCACAAGTCAATGGCCAGTCCGGTAGAATCGAC TTCCATTGGCTAATGCTAAACCCCAATGACACTGTGACATTTTCTTTTAACGGAGCATTC ATCGCCCCGGATAGGGCCAGCTTTCTCAGGGGCAAATCAATGGGGATTCAGAGTGGGGTG CAAGTTGATGCTAATTGTGAGGGTGATTGCTATCATTCAGGGGGAACCATTATCAGCAAT TTGCCCTTCCAGAACATAGACTCACGCGCCGTCGGTAAGTGCCCTCGCTATGTCAAGCAA AGGTCCCTGCTGCTGGCCACTGGAATGAAGAACGTGCCCGAGATCCCAAAGGGCAGGGGC TTATTCGGGGCCATTGCAGGTTTCATCGAAAACGGCTGGGAAGGACTAATAGATGGGTGG TACGGCTTTCGTCACCAGAACGCACAAGGGGAGGGGACAGCTGCTGATTATAAAAGTACT CAGAGCGCTATCGACCAGATTACAGGTAAGCTGAATCGGTTAATCGAGAAGACCAACCAG CAGTTCGAACTTATTGACAATGAGTTCAATGAGGTGGAGAAGCAGATTGGCAATGTGATT AATTGGACGCGGGATAGTATTACCGAGGTCTGGTCCTATAACGCCGAGTTGCTAGTGGCA ATGGAAAACCAGCACACGATAGATCTTGCAGACAGCGAAATGGATAAGTTGTACGAAAGG GTGAAACGGCAACTAAGGGAAAACGCTGAGGAAGATGGGACAGGATGCTTCGAGATCTTC CACAAATGTGACGATGACTGTATGGCCAGTATTAGAAATAACACATATGACCATTCCAAA TATCGGGAAGAGGCTATGCAAAATCGCATCCAGATTGATCCCGTAAAACTCTCCTCGGGA TACAAAGACGTGATCCTGTGGTTCTCCTTCGGAGCCTCTTGTTTCATCCTACTCGCCATC GTTATGGGGTTAGTGTTCATCTGTGTGAAGAATGGCAATATGAGGTGTACAATCTGCATT 526 ATGAATACCCAGATCCTTGTTTTCGCCCTCATCGCCATAATTCCCACCAACGCAGATAAA ATCTGTCTCGGCCACCACGCAGTGAGCAATGGCACTAAGGTCAATACCCTCACTGAACGA GGTGTCGAGGTTGTCAACGCCACTGAAACGGTAGAGAGAACGAACATCCCCCGCATATGC AGTAAAGGCAAGAAAACTGTGGATCTCGGACAGTGCGGCCTGCTGGGCACCATTACCGGC CCGCCCCAGTGCGATCAATTCCTGGAATTTTCTGCAGACCTCATCATCGAACGTCGGGAA GGGAGTGACGTGTGTTACCCCGGGAAATTCGTAAATGAGGAGGCTCTTCGCCAGATTCTG AGGGAAAGTGGGGGTATTGATAAGGAAGCAATGGGCTTTACCTATTCCGGAATTAGAACC AATGGCGCCACCTCCGCATGTAGACGGTCTGGTTCATCATTCTACGCTGAGATGAAGTGG CTGCTGTCCAACACTGACAACGCTGCATTTCCTCAGATGACTAAAAGTTACAAAAACACT CGCAAATCCCCTGCCCTTATTGTTTGGGGCATTCATCATAGTGTAAGTACAGCCGAACAA ACCAAACTGTATGGCTCAGGGAATAAATTAGTTACCGTGGGTTCATCCAACTACCAGCAG TCTTTCGTCCCTTCTCCAGGCGCTCGCCCACAAGTTAATGGGCAATCTGGGCGAATCGAT TTCCACTGGTTGATGCTGAACCCCAACGACACCGTTACCTTCAGTTTTAACGGCGCATTT ATTGCCCCCGACCGCGCAAGTTTTCTGAGGGGCAAATCAATGGGGATCCAATCTGGCGTC CAGGTGGATGCCAACTGCGAAGGCGACTGTTATCATTCCGGTGGAACAATAATCTCTAAT TTGCCGTTTCAGAACATTGATTCAAGAGCCGTGGGCAAGTGCCCACGGTACGTAAAACAG CGCTCCTTACTCCTTGCTACAGGGATGAAGAACGTGCCGGAGATCCCTAAAGGCCGAGGA CTCTTTGGTGCTATTGCAGGGTTTATAGAAAATGGCTGGGAGGGACTGATTGATGGGTGG TACGGATTCCGACACCAGAATGCCCAAGGCGAGGGTACCGCTGCAGACTACAAAAGTACC CAGAGTGCTATCGACCAGATCACCGGGAAGTTAAATCGTTTGATAGAAAAAACAAATCAA CAATTCGAGCTGATTGACAATGAGTTCAACGAGGTGGAGAAACAAATAGGAAACGTAATC AATTGGACTCGTGACAGTATAACCGAAGTCTGGAGCTACAATGCGGAGCTACTCGTCGCT ATGGAAAATCAGCATACAATCGATCTGGCGGACAGCGAGATGGATAAGCTGTACGAACGC GTGAAGAGACAACTGAGAGAAAACGCCGAGGAAGATGGCACAGGCTGCTTCGAGATTTTC CATAAGTGCGATGACGATTGCATGGCGAGTATTAGGAATAACACATATGATCACTCAAAG TATCGCGAGGAGGCGATGCAAAACAGGATCCAGATTGACCCCGTGAAATTGTCTTCTGGC TACAAGGACGTGATACTCTGGTTTTCCTTCGGGGCCTCCTGTTTCATTCTGCTGGCGATT GTGATGGGGCTGGTGTTTATATGTGTGAAAAATGGGAATATGAGATGTACTATTTGCATT 527 ATGAACACCCAGATCCTTGTGTTCGCACTGATAGCGATTATACCAACCAACGCCGACAAG ATCTGCTTAGGGCACCACGCTGTAAGTAATGGTACTAAGGTGAATACGCTGACTGAAAGA GGTGTGGAAGTGGTGAACGCCACAGAAACCGTAGAAAGGACCAACATCCCCAGAATCTGC AGCAAGGGGAAGCGGACCGTAGACCTGGGACAATGTGGACTTCTGGGAACAATTACTGGC CCTCCACAGTGCGACCAGTTCTTGGAGTTTAGCGCCGACCTCATTATCGAGCGACGGGAA GGCAGCGATGTATGTTATCCAGGCAAATTTGTGAACGAAGAAGCTCTCAGGCAGATTCTG CGGGAATCCGGCGGCATTGATAAAGAGGCTATGGGCTTTACCTACAGCGGGATCCGTACA AACGGGGCAACCTCTGCCTGTCGGAGATCTGGCTCAAGCTTTTATGCCGAGATGAAATGG CTCCTGTCTAATACTGACAATGCTGCTTTCCCACAGATGACGAAGTCCTATAAAAACACC CGGAAGTCCCCCGCCTTAATTGTATGGGGCATCCATCATTCCGTTAGCACAGCCGAACAG ACCAAGCTTTATGGATCTGGAAACAAGCTGGTGACCGTGGGCTCAAGTAACTATCAACAG TCATTCGTGCCTTCACCTGGAGCCCGCCCGCAGGTCAATGGCCTTAGCGGACGGATTGAC TTTCATTGGCTTATGCTGAATCCCAATGATACAGTGACGTTCAGCTTCAACGGCGCCTTC ATAGCCCCCGACCGTGCCAGTTTTCTTCGGGGAAAGAGCATGGGGATCCAAAGTGGCGTG CAGGTGGACGCCAATTGCGAAGGCGATTGCTATCATTCAGGCGGAACAATTATCAGTAAC CTGCCGTTTCAGAATATTGACAGTCGAGCAGTTGGGAAGTGTCCAAGGTACGTGAAACAG CGCAGCCTCCTTTTAGCCACAGGCATGAAGAATGTCCCAGAGATTCCGAAGGGCCGTGGG CTGTTTGGTGCTATTGCAGGTTTTATCGAAAATGGCTGGGAAGGACTTATTGACGGCTGG TATGGGTTTAGGCATCAGAATGCCCAGGGTGAAGGCACTGCCGCCGACTATAAGAGCACG CAAAGCGCGATCGATCAGATTACTGGCAAGTTAAATAGACTGATCGAAAAAACCAACCAA CAGTTTGAGTTGATTGATAACGAGTTTAATGAGGTCGAAAAGCAGATTGGGAACGTGATA AACTGGACCCGGGACAGCATAACCGAAGTATGGAGCTACAATGCAGAGCTGCTTGTGGCT ATGGAGAATCAGCACACAATCGATCTGGCAGACAGTGAGATGGACAAACTCTACGAGAGG GTCAAGCGGCAGCTCCGGGAAAATGCCGAGGAAGATGGTACCGGATGCTTTGAGATTTTC CATAAGTGTGACGATGATTGTATGGCCTCCATTCGCAATAACACCTATGATCACTCAAAG TATAGGGAGGAGGCAATGCAAAATCGCATCCAGATCGACCCCGTGAAGCTTAGCTCCGGA TATAAGGACGTGATCTTGTGGTTCTCTTTTGGTGCCTCCTGCTTCATCCTTCTGGCCATT GTGATGGGATTGGTATTTATTTGCGTGAAGAATGGCAATATGCGATGCACAATTTGCATC 528 ATGAATACACAGATACTGGTGTTTGCGCTGATTGCCATTATTCCAACAAATGCTGATAAA ATCTGCCTGGGGCATCACGCAGTTTCAAATGGCACCAAAGTGAACACACTTACCGAGCGA GGCGTGGAGGTGGTGAATGCCACTGAAACAGTGGAGCGTACCAATATCCCTCGTATCTGT AGCAAGGGTAAACGGACTGTCGATCTGGGCCAGTGTGGTTTACTGGGGACAATTACAGGC CCCCCTCAGTGTGATCAGTTCTTAGAGTTTTCAGCTGATCTGATCATAGAACGGAGAGAA GGCAGCGACGTGTGTTACCCTGGCAAGTTCGTGAATGAGGAGGCCCTGCGCCAAATCCTG AGAGAGTCTGGGGGGATAGATAAAGAAGCGATGGGGTTCACTTATTCTGGCATCCGAACC AATGGCGCTACGAGCGCATGCCGCAGATCTGGCTCTAGCTTTTACGCTGAGATGAAATGG CTCCTCTCTAATACGGACAATGCTGCATTTCCCCAGATGACCAAATCTTACAAGAATACC CGTAAGTCCCCAGCTCTCATCGTGTGGGGAATCCACCACTCTGTGAGTACTGCCGAGCAG ACAAAGCTCTACGGCTCTGGAAATAAGTTGGTGACCGTAGGTTCATCCAATTATCAACAG TCATTCGTGCCTAGTCCCGGTGCTCGGCCCCAAGTGAACGGCCTCTCCGGGAGGATTGAC TTCCATTGGCTGATGCTGAACCCTAACGATACAGTGACATTTTCATTTAACGGCGCGTTT ATAGCTCCTGACCGAGCTTCCTTTCTCCGAGGTAAGAGCATGGGCATCCAGAGTGGGGTA CAAGTCGATGCGAATTGCGAGGGCGATTGTTACCACAGTGGTGGCACTATCATTTCCAAC CTTCCTTTTCAGAACATTGACTCACGGGCGGTCGGCAAATGTCCTCGCTACGTGAAGCAA AGGTCCCTTCTGCTGGCCACAGGGATGAAAAACGTGCCTGAGATCCCCAAGGGGCGGGGT CTCTTTGGGGCCATCGCAGGATTTATAGAAAATGGGTGGGAGGGACTCATTAATGGCTGG TACGGATTTAGACACCAGAACGCCCAAGGGGAGGGCACTGCCGCCGATTATAAATCCACT CAGAGCGCTATCGATCAAATAACAGGTAAACTGAATCGGTTAATTGAGAAAACCAATCAA CAGTTTGAACTGATAGATAACGAGTTTAATGAAGTGGAGAAGCAGATTGGAAACGTGATC AACTGGACCAGAGACTCCATTACTGAGGTTTGGTCGTATAACGCGGAGCTGCTCGTCGCT ATGGAGAATCAACATACCATCGACCTGGCTGATAGTGAGATGGACAAGCTGTACGAGCGC GTTAAAAGACAGCTGCGTGAGAACGCTGAAGAGGATGGTACAGGATGTTTTGAGATCTTT CACAAGTGTGATGACGACTGCATGGCTAGTATCCGAAACAATACATACGACCACAGCAAA TATAGAGAAGAGGCCATGCAAAATCGTATACAAATTGATCCCGTGAAACTATCCTCCGGC TACAAGGATGTGATCTTGTGGTTTTCCTTTGGCGCATCTTGCTTCATCCTGCTGGCAATT GTAATGGGATTGGTCTTTATCTGCGTGAAGAACGGCAATATGCGGTGTACTATCTGCATC 529 ATGAACACTCAGATCCTCGTGTTTGCCTTGATCGCCATCATACCAACGAATGCAGATAAG ATCTGCCTGGGACACCATGCTGTATCAAATGGCACTAAGGTGAACACCCTGACTGAGCGG GGCGTTGAAGTGGTGAACGCCACTGAAACGGTGGAAAGGACCAATATCCCCAGAATTTGC TCAAAGGGCAAAAAAACTGTTGACCTCGGCCAGTGCGGCCTCTTAGGGACGATAACCGGT CCCCCTCAGTGTGATCAGTTCCTGGAGTTCTCAGCCGATCTGATCATTGAAAGAAGAGAA GGCTCGGACGTGTGTTATCCGGGCAAGTTCGTGAACGAAGAAGCCCTGCGCCAGATCCTC CGCGAAAGCGGGGGCATCGACAAGGAAGCCATGGGTTTCACCTACTCTGGAATTCGCACC AACGGGGCCACTTCCGCATGCCGACGGTCCGGTTCGAGCTTTTACGCTGAGATGAAGTGG CTTTTATCAAACACAGATAACGCGGCTTTCCCGCAGATGACCAAGTCCTATAAGAACACA AGAAAGTCTCCGGCCCTGATTGTCTGGGGGATCCACCATAGTGTTTCTACTGCGGAGCAG ACAAAACTTTATGGTAGCGGGAACAAACTGGTCACCGTCGGCTCCTCCAATTACCAGCAG AGTTTTGTTCCCTCCCCCGGGGCACGACCCCAAGTCAATGGGCAAAGTGGCAGGATAGAT TTCCACTGGTTGATGCTCAACCCCAATGACACCGTGACATTTAGCTTTAACGGAGCTTTT ATCGCACCAGACCGGGCATCATTCCTGCGTGGCAAGAGTATGGGTATTCAAAGTGGGGTT CAGGTAGACGCAAACTGCGAGGGCGACTGTTATCACAGTGGGGGGACCATTATCAGCAAC CTACCGTTTCAGAATATCGATAGTAGGGCAGTGGGGAAATGCCCTCGATATGTGAAGCAA CGGTCCCTGCTCCTGGCTACGGGAATGAAAAACGTCCCAGAGATTCCCAAGGGCCGGGGC CTTTTCGGCGCGATTGCTGGCTTTATTGAGAATGGGTGGGAGGGATTAATCGACGGGTGG TATGGCTTTAGGCACCAGAACGCTCAGGGCGAAGGTACGGCCGCAGATTACAAGTCCACC CAGTCCGCCATCGACCAGATTACAGGCAAGCTCAACCGTTTAATTGAGAAAACCAATCAG CAGTTCGAGCTCATCGATAACGAGTTCAATGAGGTGGAGAAACAGATTGGCAACGTGATA AACTGGACTAGGGACTCAATCACAGAGGTCTGGAGCTATAATGCCGAGCTGCTAGTTGCC ATGGAAAACCAGCATACAATCGATCTTGCCGACTCCGAAATGGACAAACTATATGAGAGA GTCAAACGTCAGCTAAGAGAGAATGCAGAAGAGGATGGCACGGGTTGCTTCGAAATTTTC CACAAGTGTGACGACGACTGCATGGCCAGCATTAGAAACAACACATACGATCATAGCAAG TATAGGGAGGAGGCGATGCAGAACAGGATTCAGATTGATCCCGTCAAGCTCTCTTCTGGC TATAAGGATGTCATTCTGTGGTTTTCTTTCGGCGCCTCATGTTTCATCCTGCTTGCAATC GTGATGGGATTAGTTTTCATTTGTGTAAAGAACGGCAATATGCGGTGTACAATCTGCATC 530 ATGAATACTCAAATCCTGGTCTTCGCCCTTATTGCGATCATACCTACCAACGCCGATAAG ATCTGCTTGGGGCACCATGCCGTCTCAAACGGCACCAAGGTCAACACTCTTACAGAACGG GGTGTAGAAGTGGTTAATGCCACTGAGACTGTCGAACGAACAAACATCCCTCGAATCTGC AGCAAAGGGAAACGGACTGTCGATCTTGGCCAGTGTGGGCTCCTGGGTACCATAACGGGG CCTCCCCAGTGCGACCAATTCTTAGAGTTCTCGGCCGATTTAATAATAGAACGCAGAGAG GGATCAGACGTATGTTACCCGGGCAAATTCGTCAATGAGGAGGCACTCCGGCAGATCCTG AGGGAGAGCGGCGGAATTGACAAAGAGGCCATGGGATTCACTTATAGTGGGATTCGTACC AATGGCGCTACAAGTGCCTGCCGTAGATCCGGGTCGAGTTTTTATGCCGAAATGAAGTGG CTACTGTCCAATACAGATAACGCTGCGTTCCCTCAGATGACTAAGTCTTACAAGAATACC AGGAAAAGCCCTGCCCTTATTGTGTGGGGAATTCACCATTCGGTGAGCACCGCGGAACAA ACAAAACTGTACGGCAGTGGGAACAAGCTCGTGACGGTAGGGTCCTCTAACTACCAACAA AGTTTCGTCCCATCCCCAGGAGCTAGACCTCAGGTGAACGGGTTAAGCGGGCGAATTGAT TTCCATTGGCTGATGCTGAACCCCAACGACACAGTGACATTTAGCTTCAATGGCGCCTTC ATAGCTCCAGACAGAGCTTCCTTTCTGAGAGGCAAAAGTATGGGAATTCAGTCTGGAGTC CAAGTGGATGCCAACTGCGAGGGGGACTGTTATCATTCTGGCGGGACCATTATCTCTAAC CTACCATTCCAGAATATAGACAGTAGGGCCGTAGGGAAGTGTCCCCGCTATGTAAAGCAG CGGAGTCTGCTGCTGGCAACAGGTATGAAGAACGTGCCCGAAATCCCCAAGGGCCGCGGA CTCTTTGGGGCTATCGCTGGGTTCATTGAGAACGGATGGGAAGGCCTCATCGATGGGTGG TATGGTTTTCGTCACCAGAACGCTCAGGGGGAAGGCACCGCCGCTGACTATAAATCTACT CAATCGGCCATCGACCAGATTACAGGGAAGCTGAATCGTCTAATCGAGAAAACCAATCAG CAATTCGAGCTTATTGACAATGAGTTCAATGAAGTGGAGAAACAGATTGGAAATGTTATA AACTGGACCCGGGACAGCATAACTGAGGTGTGGAGTTACAACGCGGAGCTCCTCGTTGCC ATGGAGAACCAGCACACCATAGATCTGGCCGATAGCGAAATGGACAAGCTGTACGAGCGG GTTAAGCGTCAACTGCGAGAGAATGCCGAAGAAGATGGCACCGGATGCTTTGAAATATTC CACAAATGCGATGATGACTGTATGGCTTCTATACGTAATAACACTTACGATCATAGCAAG TACCGAGAGGAGGCTATGCAAAACAGGATACAGATCGACCCCGTGAAACTTTCATCAGGC TATAAGGACGTTATACTGTGGTTCTCGTTCGGGGCAAGTTGCTTCATTCTGCTCGCCATT GTCATGGGCCTGGTTTTTATCTGTGTGAAGAACGGCAATATGCGGTGTACCATTTGCATC 531 ATGAATACCCAGATCTTGGTTTTCGCACTGATCGCAATTATCCCAACAAACGCAGACAAA ATTTGTCTTGGTCATCATGCCGTTTCCAACGGGACTAAAGTTAACACCCTCACGGAACGC GGAGTAGAGGTGGTCAACGCTACAGAAACCGTGGAGCGTACGAACATCCCTCGCATATGT TCCAAAGGAAAGAAGACTGTCGATCTGGGACAGTGCGGCCTATTAGGGACCATCACCGGC CCTCCTCAGTGCGATCAATTCCTTGAGTTTTCCGCGGATCTCATAATAGAGCGCAGGGAG GGTTCCGACGTCTGTTACCCTGGCAAGTTTGTGAATGAGGAAGCCTTACGGCAAATCTTG AGGAAGTCTGGCGGTATTGACAAGGAAGCGATGGGTTTTACTTATTCCGGCATCAGGACA AATGGGGCTACTTCTACTTGTCGGAGGAGTGGAAGCAGCTTCTATGCCGAGATGAAGTGG CTTCTGAGCAACACTGACAATGCCGCCTTTCCCCAGATGACAAAATCATACAAAAACACA CGCAAATCGCCCGCAATCATTGTCTGGGGCATTCATCATTCTGTCTCAACCGCCGAGCAG ACTAAACTCTATGGCTCAGGAAATAAATTAGTGACCGTGGGATCCAGCAATTACCAGCAA AGTTTCGTGCCTTCCCCAGGCGCAAGACCGCAGGTTAACGGCCTCTCTGGACGCATCGAC TTTCATTGGCTCATGCTTAACCCCAATGATACAGTGACATTCTCCTTCAATGGAGCTTTT ATCGCTCCGGACCGTGCTTGTTTCCTTCGAGGCAAGTCCATGGGAATTCAAAGTGGCGTT CAGGTTGACGCCGACTGCGAAGGTGACTGCTATCATAGCGGAGGCACTATCATCAGCAAT CTTCCATTCCAGAACATTGACTCGCGAGCCGTGGGAAAGTGCCCAAGGTATGTCAAGCAG AGGAGCCTGCTGCTGGCTACCGGCATGAAAAACGTCCCCGAAATTCCAAAAGGCCGTGGT TTGTTTGGCGCCATTGCCGGTTTTATCGAGAACGGATGGGAGGGACTGATTGACGGCTGG TACGGCTTCAGACACCAGAACGCGCAGGGAGAAGGGACGGCGGCCGATTATAAGAGCACT CAGAGCGCTATCGATCAGATTACCGGTAAATTGAATAGACTGATCGAAAAGACCAACCAG CAATTTGAACTCATTGACAATGAGTTCAACGAGGTGGAACGGCAGATAGGAAATGTCATT AACTGGACACGAGATTCTATTACTGAGGTGTGGAGTTACAACGCGGAGCTCCTAGTCGCC ATGGAGAACCAGCATACAATCGACCTGGCCGACAGCGAAATGGACAAGCTGTATGAAAGA GTAAAGAGGCAGCTGCGGGAGAACGCCGAGGAGGATGGAACCGGTTGTTTTGAGATCTTT CACAAATGCGACGATGACTGCATGGCAAGCATCCGGAACAACACTTATGACCACAGCAAG TATAGGGAGGAGGCCATGCAGAATAGAATCCAGATCGACCCAGTCAAGTTAAGCAGTGGC TACAAAGATGTTATCCTCTGGTTCTCTTTTGGAGCCTCATGTTTCATTCTTCTAGCAATC GTGATGGGTCTCGTCTTTATTTGTGTCAAAAATGGAAATATGCGCTGTACCATTTGTATT 532 ATGAACACTCAGATCCTTGTCTTTGCGCTAATTGCAATTATTCCAACGAATGCAGACAAA ATCTGCCTGGGCCATCACGCTGTTTCCAACGGAACAAAGGTGAACACACTCACGGAAAGG GGCGTCGAAGTGGTGAATGCCACGGAGACTGTTGAGAGGACCAACATCCCCAGGATCTGT AGCAAAGGAAAGCGGACAGTTGACCTGGGCCAGTGTGGCCTTCTTGGTACCATCACCGGA CCTCCCCAATGCGACCAGTTTCTGGAGTTTAGCGCAGACCTTATCATCGAGCGGCGCGAG GGGAGCGACGTCTGTTACCCGGGCAAGTTCGTAAATGAAGAGGCGCTAAGGCAGATCCTT AGGGAATCCGGGGGTATAGACAAAGAGGCAATGGGCTTTACCTACAGCGGAATCCGGACT AATGGCGCCACCTCCGCTTGTAGGCGTTCAGGATCTAGTTTCTACGCTGAGATGAAGTGG TTGTTGAGTAATACCGATAATGCGGCCTTCCCTCAGATGACCAAATCCTATAAAAATACA AGAAAAAGCCCAGCCCTGATCGTATGGGGGATCCACCATTCTGTATCTACCGCAGAACAG ACTAAGCTCTACGGGTCTGGGTCCAAATTGGTAACTGTAGGGAGCTCTAATTATCAACAG AGCTTTGTTCCGAGTCCTGGCGCCAGGCCCCAGGTGAACGGTCTGTCCGGGAGAATTGAT TTTCACTGGCTCATGCTCAATCCTAATGATACGGTTACCTTCAGCTTTAATGGAGCGTTC ATCGCACCCGATAGGGCTTCATTTTTACGTGGCAAGTCCATGGGAATCCAGTCAGGAGTC CAGGTCGACGCTAATTGCGAGGGTGATTGCTACCACAGCGGAGGAACTATCATTTCGAAC CTCCCCTTTCAGAATATTGATTCTAGGGCCGTCGGTAAATGTCCAAGATATGTGAAGCAA AGGTCTTTGCTACTCGCCACTGGAATGAAAAACGTGCCTGAAATCCCTAAAGGCCGGGGC CTGTTTGGCGCAATCGCTGGATTTATCGAGAATGGTTGGGAGGGACTGATTGACGGCTGG TATGGATTCCGGCACCAAAACGCTCAGGGGGAAGGCACTGCTGCCGATTACAAGTCCACT CAATCCGCGATTGACCAAATAACCGGTAAGCTGAATAGGCTGATCGAGAAGACAAATCAG CAGTTTGAGCTCATCGATAACGAGTTTAATGAAGTAGAAAAGCAGATTGGGAACGTTATT AATTGGACAAGAGATAGTATAACCGAGGTGTGGAGCTATAATGCGGAGCTCCTGGTGGCC ATGGAAAATCAGCATACAATAGACCTCGCCGATAGCGAAATGGATAAATTATACGAGAGA GTGAAGCGGCAGCTGAGGGAAAACGCTGAGGAGGACGGAACTGGCTGTTTTGAGATCTTT CATAAGTGCGATGATGACTGTATGGCCAGCATTCGGAACAACACCTACGATCATTCTAAG TATAGGGAGGAGGCAATGCAGAACCGAATCCAAATAGATCCTGTTAAGCTGTCTAGCGGA TATAAAGACGTGATACTTTGGTTCAGCTTCGGGGCCAGCTGTTTCATTCTGCTTGCTATC GTCATGGGACTTGTATTTATCTGCGTGAAGTCCAGAAACATGAGGTGCACTATATGTATC 533 ATGAACACTCAAATCCTGGTGTTCGCGCTGATCGCCATCATACCTACCAATGCTGACAAA ATCTGCTTGGGCCACCACGCCGTTAGCAATGGAACCAAAGTGAACACGTTGACGGAAAGA GGAGTGGAGGTGGTGAATGCCACGGAAACAGTGGAGCGGACAAACATCCCCCGGATCTGT AGTAAAGGGAAAAAGACGGTTGATCTCGGCCAGTGCGGCCTCCTGGGGACAATAACCGGG CCTCCTCAATGTGACCAGTTCCTGGAATTCTCAGCCGATTTAATCATAGAGCGGCGGGAG GGGAGTGATGTGTGTTATCCAGGGAAATTCGTGAATGAAGAAGCCTTGAGACAGATCCTT CGCGAAAGTGGAGGAATCGACAAGGAGGCCATGGGCTTTACTTATAGTGGAATCAGAACC AACGGCGCCACGTCCGCATGCCGACGCAGCGGTTCTAGCTTCTATGCCGAAATGAAGTGG CTGCTCTCCAATACCGATAATGCAGCCTTCCCCCAAATGACGAAATCTTACAAGAATACC CGCAAAAGTCCTGCTTTGATTGTCTGGGGCATCCACCACAGCGTCTCTACTGCCGAACAA ACAAAGTTATACGGATCAGGCAACAAACTGGTCACCGTAGGTTCCAGCAACTACCAACAG TCATTTGTCCCGAGCCCTGGAGCCCGCCCACAGGTGAACGGGCAGTCCGGCCGAATTGAC TTTCACTGGCTGATGCTCAACCCGAACGATACTGTGACCTTCAGCTTCAATGGCGCGTTC ATTGCACCTGACCGTGCATCATTCTTGAGGGGCAAAAGCATGGGGATCCAGTCTGGAGTC CAGGTCGACGCAAATTGCGAAGGAGATTGTTATCACAGCGGGGGCACGATTATCTCAAAT CTCCCCTTTCAAAATATAGATAGCCGAGCAGTTGGCAAATGCCCTCGCTACGTGAAACAA AGGAGCCTGCTCCTGGCTACCGGGATGAAGAACGTACCTGAAATCCCCAAGGGACGCGGA CTTTTCGGCGCTATTGCTGGGTTCATAGAAAACGGCTGGGAAGGGTTGATCGACGGCTGG TATGGCTTCAGACACCAGAATGCTCAGGGAGAAGGCACAGCAGCCGACTACAAATCAACC CAGTCTGCCATCGATCAGATTACAGGAAAGCTGAATCGGCTCATCGAGAAAACTAACCAG CAGTTCGAACTCATCGACAATGAGTTTAACGAGGTCGAAAAACAGATTGGTAATGTGATC AACTGGACTAGGGACTCCATTACAGAGGTTTGGTCCTATAATGCCGAGCTTTTGGTTGCC ATGGAAAACCAACATACCATCGACCTGGCCGATAGCGAGATGGACAAGTTGTACGAGAGG GTAAAAAGGCAGCTCAGAGAAAACGCCGAGGAAGATGGAACCGGTTGTTTCGAAATTTTT CATAAGTGCGATGACGACTGTATGGCTTCAATTCGAAACAATACTTACGATCACAGCAAG TACCGCGAAGAGGCCATGCAGAATAGGATTCAGATTGATCCTGTTAAGTTGTCATCCGGC TATAAGGATGTAATCTTATGGTTTAGTTTCGGCGCTAGCTGCTTCATACTGCTGGCAATC GTGATGGGGCTGGTATTTATATGCGTCAAAAATGGGAATATGCGCTGTACCATCTGCATC 534 ATGAATACTCAAATCTTGGTCTTTGCACTGATCGCCATTATTCCTACTAACGCCGATAAA ATTTGCTTGGGTCATCACGCCGTGTCAAATGGCACTAAAGTTAATACCTTAACAGAGCGC GGAGTAGAGGTGGTGAATGCAACGGAGACTGTTGAGCGGACCAATATACCCCGCATTTGT AGTAAAGGCAAGAAAACAGTGGACCTGGGCCAATGCGGGTTGCTTGGGACGATCACCGGC CCCCCGCAGTGCGATCAGTTCTTAGAATTCTCCGCTGACCTAATCATCGAAAGACGGGAG GGCAGCGATGTGTGTTATCCTGGCAAATTCGTCAACGAGGAAGCCCTCAGGCAGATTCTT CGCAAGTCAGGGGGTATTGATAAGGAGGCGATGGGATTCACATACTCCGGAATTCGAACA AACGGCGCTACAAGTACTTGTAGGAGGAGCGGGAGTTCATTCTACGCAGAGATGAAGTGG CTGCTCAGCAACACCGACAACGCAGCGTTCCCACAGATGACCAAAAGCTATAAAAATACC CGAAAGAGTCCCGCAATCATCGTATGGGGAATTCATCACAGTGTCTCTACCGCTGAGCAG ACCAAGTTGTATGGCTCCGGCAACAAGCTCGTTACCGTTGGCAGCTCAAATTACCAACAG TCCTTCGTCCCCTCCCCAGGGGCAAGGCCCCAAGTCAACGGCCTGTCCGGCAGAATTGAC TTCCACTGGCTCATGCTAAACCCCAATGATACGGTCACCTTCAGTTTTAATGGGGCATTC ATCGCACCCGACAGAGCCTGTTTTCTGCGAGGTAAATCAATGGGTATACAATCCGGGGTC CAGGTCGACGCTGACTGCGAGGGCGACTGCTATCATTCGGGAGGCACCATTATTTCCAAC CTGCCTTTCCAGAACATTGATTCCAGAGCCGTGGGCAAGTGTCCTCGGTACGTGAAACAA CGATCTCTGCTTCTGGCTACCGGAATGAAGAACGTGCCCGAGATCCCCAAGGGACGAGGC CTGTTCGGGGCCATTGCCGGATTTATTGAGAATGGCTGGGAGGGTCTCATCGATGGATGG TACGGCTTCAGGCACCAGAACGCACAAGGTGAAGGCACAGCTGCTGATTACAAATCCACC CAGAGTGCAATTGACCAGATCACCGGAAAACTCAATAGACTGATTGAAAAAACCAACCAA CAGTTTGAATTGATTGATAATGAGTTTAACGAAGTCGAACGGCAGATTGGTAATGTGATC AATTGGACCCGGGATTCCATTACAGAGGTTTGGTCCTACAACGCCGAGCTGCTCGTCGCA ATGGAAAATCAGCACACCATAGATCTGGCCGACTCCGAGATGGACAAGCTTTACGAAAGG GTGAAGAGACAGCTCAGGGAGAACGCCGAAGAGGACGGAACAGGGTGTTTCGAAATCTTC CATAAGTGCGACGATGATTGTATGGCTTCTATCCGGAACAACACCTATGATCACTCCAAA TATAGAGAGGAAGCAATGCAGAACAGGATTCAAATCGACCCTGTCAAACTCTCAAGTGGG TACAAGGACGTAATCCTATGGTTCAGCTTTGGCGCCAGCTGTTTTATTCTGCTGGCAATC GTGATGGGTTTGGTGTTTATCTGCGTCAAGAATGGCAACATGAGGTGTACCATTTGCATC 535 ATGAATACACAGATCCTGGTCTTCGCCCTTATCGCTATCATCCCCACAAACGCCGACAAG ATATGCCTGGGCCACCACGCCGTTAGCAACGGCACCAAAGTAAACACTCTCACTGAAAGG GGTGTGGAAGTTGTGAACGCAACAGAAACCGTAGAACGCACGAACATTCCAAGAATTTGC TCAAAGGGGAAACGTACAGTCGATCTAGGACAGTGCGGCCTGCTCGGCACCATAACCGGG CCCCCCCAATGCGATCAATTTCTGGAGTTCTCTGCCGATCTTATCATCGAGCGTCGGGAA GGGAGCGATGTGTGCTACCCCGGCAAATTTGTGAACGAGGAGGCCCTCAGACAGATCTTA AGAGAGTCTGGAGGGATTGACAAAGAGGCCATGGGGTTCACATACTCCGGCATACGTACG AATGGGGCCACGAGTGCTTGTCGGAGGAGCGGTTCAAGTTTCTACGCGGAGATGAAATGG CTGCTGAGCAATACCGATAACGCCGCCTTCCCCCAGATGACCAAAAGTTATAAAAATACA AGGAAATCACCCGCCCTTATCGTTTGGGGAATTCATCACTCCGTCAGTACCGCCGAACAG ACTAAGCTCTATGGATCGGGTTCAAAGCTAGTGACCGTGGGCTCAAGCAATTACCAGCAA TCCTTTGTACCAAGCCCTGGGGCCCGTCCCCAAGTGAACGGATTAAGCGGTAGGATTGAC TTCCATTGGTTGATGCTCAATCCGAATGATACGGTGACCTTCAGTTTCAACGGGGCGTTC ATAGCTCCTGATCGCGCGAGCTTCCTCCGGGGAAAATCGATGGGAATTCAGTCAGGCGTT CAGGTGGACGCCAATTGTGAAGGAGACTGCTACCATAGCGGAGGGACTATAATTTCCAAT CTGCCTTTTCAGAACATTGACTCCCGCGCTGTGGGGAAGTGTCCCCGGTACGTGAAGCAA CGCTCCCTGCTTCTCGCCACAGGCATGAAGAACGTACCTGAGATTCCTAAGGGCCGGGGG CTTTTCGGCGCGATTGCTGGATTCATCGAAAACGGCTGGGAAGGTTTAATAGATGGCTGG TATGGCTTCAGGCACCAGAATGCACAGGGCGAGGGGACCGCGGCCGACTATAAGTCTACC CAAAGTGCTATTGATCAGATAACCGGAAAGCTTAACCGCCTGATCGAGAAAACCAATCAA CAGTTTGAACTTATCGACAACGAATTCAACGAGGTTGAGAAGCAGATTGGGAACGTCATT AATTGGACCCGAGATTCGATCACAGAGGTGTGGAGCTACAACGCCGAGCTGCTGGTCGCG ATGGAAAATCAGCATACAATCGACTTGGCCGATAGTGAGATGGACAAACTATACGAGAGA GTGAAACGGCAGCTGAGGGAGAACGCCGAAGAGGACGGCACCGGGTGCTTTGAGATTTTT CACAAGTGCGATGACGATTGTATGGCTTCCATCAGGAATAATACTTACGACCACAGTAAG TATCGCGAAGAGGCTATGCAAAACCGCATTCAGATCGACCCCGTCAAACTCTCATCGGGC TATAAAGATGTGATACTCTGGTTTTCTTTTGGTGCATCATGCTTCATTCTTTTGGCAATA GTGATGGGGCTGGTGTTCATCTGCGTAAAGAACGGTAACATGAGATGCACTATCTGTATT 536 ATGAATACACAGATCTTAGTGTTTGCTTTAATAGCTATTATTCCAACCAATGCCGATAAA ATCTGTCTGGGACACCACGCCGTGAGCAATGGGACGAAAGTGAACACTCTTACCGAACGA GGAGTCGAGGTTGTCAATGCTACGGAAACTGTGGAAAGGACCAACATCCCAAGGATCTGC AGCAAAGGCAAAAAAACTGTAGATCTGGGGCAGTGTGGACTGCTGGGGACCATTACCGGA CCCCCCCAGTGCGACCAGTTCTTGGAGTTTTCCGCCGATCTGATTATTGAGCGGCGCGAG GGGTCTGATGTGTGCTATCCTGGTAAATTTGTCAACGAAGAGGCGCTGCGACAAATTCTC CGCAAAAGTGGGGGAATCGACAAGGAAGCCATGGGCTTCACATACTCTGGCATTCGAACA AATGGGGCCACTTCCACATGCAGGCGGTCTGGGTCTTCATTTTATGCCGAGATGAAGTGG CTTCTTTCTAATACTGACAACGCCGCCTTCCCCCAAATGACCAAGTCCTACAAAAACACC CGGAAGTCCCCAGCCATTATCGTCTGGGGAATCCATCACAGCGTTTCTACAGCCGAACAG ACCAAGCTCTACGGATCAGGAAACAAACTGGTTACAGTGGGTAGCAGCAACTATCAGCAG TCGTTCGTTCCTTCTCCTGGGGCGCGGCCGCAAGTAAACGGGCTCAGTGGGCGTATCGAT TTCCACTGGCTGATGCTGAACCCAAACGACACAGTCACCTTCAGCTTTAATGGAGCCTTC ATCGCCCCTGATAGGGCCTGCTTTCTGCGGGGAAAATCCATGGGCATCCAAAGCGGAGTG CAGGTCGACGCCGATTGCGAAGGGGACTGCTACCATTCTGGTGGGACCATCATCTCCAAC CTCCCATTTCAGAACATTGACTCCCGGGCGGTCGGAAAATGCCCACGTTACGTGAAGCAG CGCAGTCTCTTACTCGCCACTGGGATGAAGAACGTGCCCGAAATTCCAAAGGGGCGTGGT CTGTTTGGGGCGATTGCCGGCTTCATTGAGAACGGCTGGGAGGGGCTTATCGACGGCTGG TACGGATTCCGTCACCAGAATGCCCAGGGTGAGGGCACCGCAGCAGACTATAAAAGCACA CAGAGCGCCATTGACCAAATCACTGGGAAGCTGAATCGCCTGATTGAGAAAACTAACCAG CAGTTTGAACTCATAGATAATGAATTTAACGAAGTCGAAAGGCAGATTGGCAACGTAATT AATTGGACTCGCGACTCAATCACTGAGGTCTGGAGTTACAATGCAGAACTGCTTGTCGCT ATGGAGAACCAGCATACCATTGACCTGGCTGATAGCGAGATGGATAAACTGTACGAAAGG GTGAAGCGACAGCTCCGCGAGAACGCAGAGGAGGACGGGACCGGCTGTTTCGAGATCTTT CACAAGTGTGACGACGACTGTATGGCTTCGATTCGGAACAACACCTATGACCACTCCAAA TATAGGGAAGAGGCTATGCAGAATAGGATCCAAATCGATCCTGTGAAGCTGAGCTCCGGC TACAAAGACGTAATCCTGTGGTTCTCTTTTGGCGCCTCGTGTTTTATCCTACTCGCCATC GTCATGGGTTTAGTTTTTATCTGCGTAAAAAATGGAAATATGAGATGTACTATCTGCATC 537 ATGAACACGCAGATCCTTGTCTTCGCCCTGATTGCCATTATACCCACTAACGCCGATAAA ATTTGCTTGGGCCACCACGCCGTGTCCAATGGAACAAAAGTGAATACTTTGACCGAGAGG GGTGTCGAAGTCGTCAACGCCACCGAGACTGTCGAACGGACAAATATACCGCGTATCTGT TCTAAAGGGAAGCGAACCGTGGACCTGGGTCAATGCGGACTGCTGGGGACTATTACAGGG CCCCCTCAGTGCGATCAGTTTCTGGAATTTAGCGCTGACCTCATTATTGAAAGGAGGGAG GGATCAGATGTGTGTTACCCAGGTAAGTTTGTCAATGAGGAAGCCCTCCGACAGATTCTC AGGGAATCTGGAGGCATTGATAAAGAGGCTATGGGGTTCACCTATTCAGGCATCAGGACC AATGGGGCTACCAGCGCTTGCCGCCGGAGCGGATCATCTTTTTATGCCGAGATGAAATGG CTACTGTCAAACACCGACAACGCCGCATTCCCACAGATGACCAAGAGTTACAAGAATACA CGCAAGTCACCCGCCCTCATCGTCTGGGGCATCCATCATTCCGTGAGCACAGCCGAGCAG ACGAAGCTCTACGGATCGGGCAGCAAGCTCGTAACCGTCGGGAGCTCTAACTATCAGCAA TCTTTTGTGCCCTCCCCCGGAGCCCGGCCACAGGTCAATGGACTATCCGGGCGCATCGAT TTCCACTGGCTGATGTTGAACCCGAACGACACCGTGACATTTTCATTCAATGGGGCATTC ATCGCGCCAGACCGCGCGTCCTTTCTGAGGGGAAAGTCCATGGGTATCCAGTCTGGTGTA CAGGTGGATGCCAACTGTGAGGGTGACTGCTACCATAGTGGAGGAACAATTATCTCCAAC TTGCCATTCCAAAACATCGACAGTAGAGCTGTTGGTAAATGTCCCAGGTACGTGAAGCAA AGGTCATTGCTGCTGGCCACTGGGATGAAGAATGTGCCCGAAATTCCAAAAGGAAGGGGG CTTTTCGGGGCAATCGCCGGCTTCATTGAGAATGGCTGGGAAGGCCTCATCGACGGGTGG TACGGGTTTAGGCATCAAAACGCGCAGGGGGAGGGGACAGCTGCTGATTACAAGAGTACA CAGAGCGCAATCGACCAGATCACCGGGAAACTAAATCGCCTCATCGAGAAGACTAATCAG CAGTTCGAACTGATCGACAACGAGTTCAACGAGGTCGAAAAACAGATTGGTAACGTCATT AACTGGACCAGAGATTCCATAACCGAAGTCTGGTCCTATAACGCAGAACTGCTGGTAGCC ATGGAGAACCAGCACACTATCGACCTGGCAGACTCGGAAATGGATAAACTGTACGAGAGG GTGAAGCGGCAGCTCCGGGAGAACGCTGAAGAAGATGGTACCGGCTGTTTCGAAATTTTT CACAAATGTGACGATGATTGTATGGCCTCTATACGCAACAATACCTACGATCACTCCAAA TACAGGGAGGAGGCTATGCAGAATCGTATCCAGATCGATCCGGTAAAACTGAGTAGCGGA TATAAGGATGTGATCCTGTGGTTCAGCTTCGGGGCTAGTTGCTTTATTCTGTTGGCAATT GTGATGGGCCTGGTGTTCATTTGCGTCAAAAATGGCAACATGCGCTGCACCATTTGTATC 538 ATGAACACCCAAATATTAGTGTTCGCATTGATTGCGATTATCCCAACCAACGCAGATAAG ATCTGCTTGGGACATCACGCTGTCAGCAACGGGACCAAGGTGAACACGTTGACAGAGAGG GGCGTAGAAGTGGTCAACGCCACTGAGACAGTGGAACGCACCAACATACCGCGGATCTGC TCCAAGGGAAAGCGCACGGTGGATCTTGGCCAGTGCGGCCTGCTGGGTACGATAACTGGA CCTCCCCAGTGCGACCAGTTCCTGGAGTTCTCCGCCGACCTCATCATCGAAAGGAGAGAA GGTAGCGATGTCTGCTACCCAGGGAAATTCGTTAACGAAGAGGCCCTTAGACAAATCCTG AGAGAATCTGGCGGGATCGATAAGGAGGCAATGGGATTTACTTACTCAGGAATTAGGACT AACGGGGCTACCTCTGCGTGCCGACGGTCCGGTTCGAGCTTCTATGCCGAGATGAAATGG CTTTTGAGCAACACCGATAATGCTGCTTTTCCCCAGATGACTAAGTCCTATAAGAATACC AGAAAAAGCCCCGCCTTAATTGTGTGGGGCATCCACCACTCAGTGAGTACAGCCGAACAA ACGAAACTGTACGGCTCTGGTTCCAAGTTGGTCACAGTCGGATCCTCAAATTATCAGCAG AGCTTCGTACCCTCTCCGGGTGCGAGACCACAGGTGAACGGCCTGAGTGGTCGGATTGAC TTCCACTGGCTCATGCTGAACCCCAACGATACCGTAACTTTCTCTTTCAACGGAGCCTTT ATAGCTCCTGATAGAGCTTCTTTTCTGCGTGGGAAGTCCATGGGGATCCAGAGCGGCGTG CAGGTGGACGCGAACTGTGAGGGTGACTGCTATCACTCAGGAGGAACAATTATCTCGAAT CTTCCTTTTCAAAACATCGACTCCCGAGCCGTCGGAAAATGCCCTCGCTATGTGAAACAG CGGAGCTTGTTGCTCGCCACGGGGATGAAGAACGTCCCTGAAATACCGAAGGGGCGGGGC CTGTTTGGAGCAATCGCAGGATTTATCGAGAACGGGTGGGAAGGGCTTATTGATGGGTGG TATGGCTTCCGCCACCAAAACGCTCAAGGCGAGGGGACTGCTGCTGATTATAAATCGACA CAGTCTGCTATTGACCAGATTACAGGAAAGCTCAACCGATTGATAGAAAAGACTAACCAG CAGTTTGAGCTGATCGATAATGAATTTAACGAGGTGGAGAAGCAGATCGGGAATGTGATC AACTGGACCAGAGATTCCATCACTGAAGTTTGGAGTTACAACGCCGAGCTCCTGGTGGCT ATGGAAAATCAGCATACCATCGACCTCGCTGACAGTGAGATGGACAAGCTCTATGAAAGA GTTAAGCGACAGCTGCGAGAGAATGCCGAGGAGGATGGTACAGGCTGCTTTGAGATTTTC CACAAGTGTGATGATGACTGTATGGCCTCAATACGGAATAATACATATGATCACTCCAAG TATCGGGAGGAAGCCATGCAGAACCGTATCCAGATCGACCCTGTGAAACTGAGCTCTGGA TACAAGGATGTCATACTCTGGTTCTCATTCGGTGCTTCTTGTTTTATTCTGCTGGCCATT GTGATGGGCCTCGTGTTTATATGCGTAAAGTCCCGCAACATGAGATGCACCATCTGTATC 539 ATGAATACTCAGATACTGGTATTCGCTCTCATTGCTATTATTCCTACGAACGCAGATAAG ATTTGCCTAGGCCATCATGCTGTCTCTAACGGCACTAAGGTCAACACCCTGACCGAGCGC GGAGTGGAGGTAGTTAACGCAACTGAAACAGTCGAACGCACCAATATTCCCAGAATCTGC TCGAAGGGAAAGAAGACCGTCGATCTGGGGCAATGTGGGCTTCTCGGCACCATCACGGGC CCTCCACAGTGTGACCAGTTTCTGGAATTTTCCGCCGACCTGATCATAGAGCGCCGGGAA GGATCCGATGTGTGTTATCCCGGGAAGTTCGTGAACGAGGAAGCACTGCGACAGATCCTG AGGGAGTCCGGCGGGATTGACAAGGAGGCCATGGGCTTCACTTATAGCGGTATACGTACC AACGGTGCAACCAGTGCTTGCAGGCGATCCGGGTCCTCCTTCTACGCTGAGATGAAGTGG CTCCTCTCCAATACAGACAACGCCGCCTTTCCACAGATGACTAAAAGTTATAAGAACACA CGCAAGTCCCCCGCGCTGATCGTGTGGGGGATTCATCATAGCGTGAGCACCGCGGAGCAG ACAAAACTCTACGGAAGCGGTAACAAGCTGGTAACAGTGGGATCTTCTAACTACCAACAG AGTTTCGTGCCTTCCCCAGGTGCGCGCCCCCAGGTAAACGGACAGAGTGGGAGAATCGAC TTCCACTGGCTGATGCTGAATCCCAACGATACTGTCACCTTTAGTTTTAATGGTGCATTT ATCGCCCCTGATAGAGCATCCTTCTTACGGGGGAAGAGTATGGGGATTCAGTCAGGCGTG CAGGTTGACGCTAACTGCGAGGGCGATTGTTACCACTCGGGCGGGACTATAATCTCGAAC CTTCCCTTTCAAAACATAGATAGCCGGGCCGTGGGCAAATGTCCGAGATACGTGAAACAG AGGAGTCTGTTGCTGGCTACGGGCATGAAGAACGTGCCAGAAATTCCTAAGGGCCGCGGT CTGTTCGGAGCAATCGCAGGGTTCATCGAGAATGGCTGGGAAGGGCTGATCGATGGTTGG TATGGATTCAGACACCAGAACGCGCAGGGGGAGGGAACAGCCGCTGACTATAAATCCACA CAGAGCGCTATAGATCAAATCACAGGGAAACTTAACAGGCTGATCGAGAAAACAAACCAG CAGTTTGAGTTGATTGATAATGAGTTCAACGAGGTGGAGAAGCAAATCGGCAACGTCATC AATTGGACTCGCGATTCTATCACTGAGGTATGGAGCTACAATGCAGAGCTGCTCGTAGCG ATGGAGAATCAGCATACAATTGATCTGGCCGACTCCGAAATGGACAAGCTGTATGAGCGC GTAAAGAGACAACTTAGAGAAAATGCCGAGGAAGATGGCACTGGCTGCTTCGAAATCTTT CATAAATGCGATGATGACTGTATGGCATCTATCAGAAACAACACTTATGACCACTCCAAG TATAGGGAAGAAGCTATGCAGAATAGAATCCAGATCGATCCCGTAAAACTTAGTTCCGGG TACAAGGACGTTATTCTTTGGTTTTCTTTCGGCGCAAGCTGTTTCATCCTTCTTGCAATC GTAATGGGTCTCGTCTTCATCTGCGTTAAAAATGGCAACATGCGTTGCACAATTTGCATT 540 ATGAATACCCAGATCCTGGTCTTTGCGCTGATCGCTATTATCCCAACTAACGCCGATAAA ATCTGCCTGGGCCACCACGCTGTCAGCAATGGCACAAAGGTAAATACCCTAACAGAGCGG GGGGTGGAAGTCGTTAATGCTACTGAGACCGTGGAACGAACAAATATTCCTAGGATCTGT TCCAAGGGCAAGCGCACTGTGGACTTGGGTCAGTGCGGCTTACTTGGTACAATCACTGGG CCGCCACAGTGCGACCAGTTTCTCGAGTTCTCGGCCGATCTGATCATAGAAAGAAGGGAG GGCAGCGACGTGTGCTACCCCGGCAAGTTTGTTAACGAGGAGGCACTGCGGCAGATCCTG AGAGAAAGCGGAGGCATCGACAAAGAGGCAATGGGGTTCACCTACTCTGGCATTAGGACT AACGGTGCAACTTCTGCCTGCCGGAGAAGCGGTTCTTCCTTCTACGCCGAAATGAAGTGG CTGCTGTCCAATACTGACAACGCTGCCTTTCCTCAGATGACAAAGAGTTACAAAAACACA CGGAAAAGCCCAGCTCTGATCGTGTGGGGCATCCACCATAGTGTAAGCACAGCTGAACAG ACGAAGCTGTACGGGTCTGGCAATAAACTTGTCACAGTTGGATCGTCCAATTACCAACAG AGCTTCGTCCCCAGTCCAGGTGAGAGACCTCAGGTTAACGGCCTCTCGGGGAGAATCGAC TTCCACTGGCTGATGCTTAACCCCAACGACACAGTAACCTTCTCCTTTAACGGCGCCTTT ATTGCTCCTGATAGGGCCTCCTTTTTGAGAGGAAAAAGTATGGGCATCCAAAGCGGGGTG CAGGTGGACGCCAACTGTGAAGGCGACTGCTACCACTCGGGGGGCACCATAATATCCAAC CTACCTTTTCAGAATATTGACTCTCGGGCCGTGGGGAAGTGTCCTCGTTACGTGAAGCAG CGAAGCCTCCTACTCGCAACCGGCATGAAGAACGTCCCAGAGATCCCAAAGGGTCGGGGC CTGTTCGGTGCCATTGCCGGGTTTATAGAAAACGGGTGGGAAGGCCTGATCGATGGCTGG TATGGCTTCCGCCATCAGAACGCACAGGGTGAGGGCACAGCAGCAGACTATAAAAGCACT CAATCGGCCATCGACCAGATCACGGGGAAGTTAAATAGGCTGATTGAAAAGACAAACCAA CAATTCGAACTTATTGATAACGAGTTTAACGAAGTGGAGAAGCAGATAGGAAACGTTATC AATTGGACGCGAGATTCCATAACAGAAGTTTGGTCATATAATGCCGAGCTCCTAGTCGCC ATGGAAAATCAGCACACTATTGATCTGGCTGATTCCGAGATGGATAAATTATATGAGAGA GTGAAGCGCCAGCTTAGGGAAAACGCCGAAGAGGACGGAACTGGGTGTTTCGAGATCTTT CATAAATGCGATGATGACTGCATGGCCTCTATTCGGAATAACACATACGATCACTCCAAG TATCGGGAGGAGGCGATGCAGAACAGAATTCAGATTGATCCAGTGAAGCTGTCCAGCGGA TACAAAGACGTGATACTATGGTTCAGCTTTGGTGCTAGTTGCTTTATCCTGTTGGCGATC GTCATGGGCCTGGTATTCATTTGCGTGAAGAATGGTAACATGCGCTGCACCATATGTATT 541 ATGAACACACAGATACTGGTGTTCGCACTGATAGCCATAATACCTACCAATGCTGATAAA ATTTGTCTTGGTCACCATGCCGTCAGCAATGGAACAAAAGTCAATACTCTGACAGAGAGG GGAGTCGAAGTGGTGAACGCAACAGAGACGGTAGAACGGACAAACATTCCAAGAATCTGT TCCAAAGGTAAGAGGACGGTCGATCTCGGACAGTGCGGCCTATTAGGAACTATTACTGGT CCTCCGCAGTGCGACCAGTTTCTGGAATTTAGCGCAGACTTGATTATAGAGCGGCGAGAA GGGTCCGATGTATGCTATCCCGGCAAATTCGTGAATGAGGAGGCCCTGCGACAGATTTTG AGAGAAAGCGGGGGGATTGATAAAGAAGCGATGGGGTTTACATATTCAGGCATCAGGACC AATGGCGCTACCTCAGCTTGCCGAAGAAGTGGTAGCTCTTTTTATGCCGAAATGAAGTGG CTTCTTTCAAACACTGATAACGCAGCCTTCCCACAGATGACCAAGAGCTACAAGAATACT CGTAAATCACCAGCCCTAATTGTGTGGGGTATCCACCATTCAGTCTCTACCGCAGAACAA ACAAAACTGTACGGCAGCGGGAACAAGCTAGTGACCGTTGGATCCAGCAATTACCAGCAA AGCTTTGTCCCTTCCCCCGGCGCACGTCCACAGGTAAACGGCTTGAGCGGGAGAATTGAT TTCCACTGGCTAATGCTAAATCCCAACGATACCGTTACTTTTAGCTTCAATGGGGCTTTC ATTGCCCCAGATAGAGCCTCTTTCCTGAGAGGTAAAAGTATGGGCATCCAATCCGGGGTG CAGGTGGATGCGAATTGTGAAGGCGATTGTTACCACAGCGGGGGGACCATTATTTCCAAC TTACCCTTCCAAAACATCGATTCGCGAGCAGTGGGCAAATGTCCCCGGTATGTCAAGCAG AGGTCGCTGTTGCTGGCCACCGGCATGAAAAATGTCCCTGAGATTCCAAAAGGTCGCGGT TTGTTTGGCGCTATTGCGGGATTTATCGAGAACGGCTGGGAGGGGCTGATTGACGGGTGG TACGGGTTCAGACACCAGAACGCTCAGGGCGAGGGAACCGCTGCGGATTATAAAAGCACG CAGTCGGCCATAGACCAGATCACAGGCAAGCTCAATAGGCTCATCGAGAAGACGAATCAG CAATTCGAATTGATAGATAACGAATTCAACGAGGTGGAGAAACAGATTGGGAATGTGATC AATTGGACAAGGGATTCAATTACGGAAGTGTGGTCCTATAACGCCGAGCTGCTCGTGGCC ATGGAGAATCAGCATACAATCGATCTGGCCGACAGTGAGATGGATAAACTCTACGAACGT GTGAAGCGGCAGCTACGCGAGAACGCCGAGGAAGATGGGACAGGCTGTTTTGAGATCTTC CACAAGTGCGACGACGACTGTATGGCGTCAATCCGCAATAACACATACGACCACAGCAAG TACCGAGAGGAAGCCATGCAAAACAGGATCCAAATCGATCCTGTAAAGCTTTCCTCTGGG TATAAAGACGTCATTCTTTGGTTCTCTTTTGGAGCCAGTTGCTTCATCCTTCTAGCCATT GTGATGGGGCTGGTATTCATCTGCGTGAAAAATGGGAATATGCGATGTACCATATGCATT 542 ATGAATACCCAGATCCTCGTTTTTGCTCTGATCGCAATTATTCCCACTAATGCAGACAAA ATCTGTCTCGGTCATCATGCTGTGTCTAATGGAACGAAGGTCAATACCCTGACCGAACGC GGTGTCGAAGTGGTCAATGCGACAGAAACTGTAGAACGAACCAATATCCCTAGGATTTGT TCCAAGGGGAAGAAGACTGTTGACTTGGGGCAATGCGGGCTCCTAGGCACCATTACGGGC CCCCCCCAATGTGACCAGTTCCTAGAGTTTAGCGCAGATCTGATCATCGAAAGAAGGGAA GGCTCCGATGTGTGCTATCCCGGGAAGTTCGTGAATGAAGAGGCGCTGAGGCAGATTCTC AGAGAGAGCGGCGGTATTGAGAAAGAAGCTATGGGATTTACATATAGCGGGATTCGCGCA AACGGCGCAACTAGTGCGTGTCGACGCAGCGGTTCTTCTTTCTATGCCGAGATGAAGTGG TTACTAAGCAACACCGATAACGCCGCGTTCCCCCAGATGACCAAGTCTTATAAGAACACA CGCAAATCCCCCGCGCTCATTGTGTGGGGAATTCACCACAGCGTCTCTACTGCAGAGCAG ACAAAACTGTACGGTTCAGGGAATAAGCTCGTAACTGTAGGGTCAAGTAACTACCAGCAG TCCTTTGTCCCTTCTCCAGGGGCTCGGCCTCAGGTCAATGGGCTGAGCGGCCGGATCGAT TTCCACTGGCTGATGCTGAATCCCAACGACACCGTGACTTTCTCTTTCAACGGGGCCTTT ATCGCCCCAGATCGGGCCAGCTTTCTGAGAGGGAAGTCAATGGGAATCCAGTCTGGAGTC CAGGTGGATGCGAACTGTGAAGGGGATTGCTACCACAGCGGCGGGACTATCATCTCCAAC CTTCCATTCCAAAACATTGACTCTCGCGCCGTTGGCAAGTGTCCACGATACGTCAAGCAG AGGTCTCTGCTCCTGGCTACCGGAATGAAGAATGTGCCCGAGATACCCAAAGGCCGTGGC CTGTTCGGCGCGATAGCTGGCTTTATTGAAAACGGATGGGAGGGATTGATAGACGGCTGG TACGGCTTTCGCCATCAGAACGCGCAGGGCGAAGGAACCGCCGCCGATTATAAATCAACA CAGTCAGCTATCGACCAGATAACCGGCAAGCTGAACCGATTAATTGAAAAAACAAACCAG CAGTTTGAACTGATCGATAATGAATTCAACGAAGTGGAAAAACAGATTGGGAATGTTATA AATTGGACTCGGGACTCCATCACTGAAGTTTGGTCTTACAATGCCGAATTACTGGTTGCC ATGGAAAATCAACACACTATCGATCTCGCGGACAGCGAAATGGACAAGCTTTACGAACGC GTTAAACGGCAGCTTCGTGAGAATGCGGAAGAGGATGGAACGGGCTGCTTCGAGATCTTC CATAAATGCGACGACGATTGTATGGCCTCAATTAGGAATAACACCTACGATCACAGCAAG TACCGGGAGGAGGCCATGCAGAACCGCATTCAAATTGATCCCGTCAAACTCTCGAGCGGG TATAAAGATGTGATCTTGTGGTTCTCTTTTGGTGCTTCCTGCTTTATCCTACTGGCCATT GTCATGGGACTGGTGTTCATCTGCGTCAAAAACGGGAACATGCGCTGTACCATCTGTATT 543 ATGAACACCCAGATCCTTGTCTTTGCTCTGATTGCTATCATCCCTACAAATGCGGACAAG ATTTGTCTGGGTCATCATGCAGTATCCAACGGAACCAAAGTCAACACCCTAACCGAACGC GGCGTAGAAGTGGTCAACGCCACCGAGACCGTGGAACGCACAAATATTCCTAGGATCTGC TCAAAAGGTAAAAAGACAGTGGATTTGGGCCAGTGTGGTCTGCTGGGGACTATAACTGGC CCCCCCCAATGCGATCAGTTCCTTGAATTTAGCGCCGATCTCATTATAGAACGGCGGGAG GGCAGCGATGTTTGCTATCCAGGAAAGTTTGTCAATGAAGAAGCACTAAGGCAGATTCTG AGAGAATCTGGAGGAATCGACAAGGAGGCCATGGGATTCACGTACTCCGGCATTCGCACA AATGGGGCCACCTCAGCTTGTAGGCGCAGTGGCAGCAGCTTTTACGCGGAGATGAAGTGG TTGCTTTCCAATACAGATAACGCTGCATTCCCCCAGATGACAAAAAGCTACAAGAATACA CGAAAATCCCCCGCTCTGATAGTGTGGGGGATCCACCATAGTGTGTCAACCGCCGAGCAA ACGAAGTTGTATGGCTCCGGAAACAAATTGGTGACTGTCGGTTCATCCAACTACCAGCAG TCTTTTGTGCCTTCTCCCGGGGCCCGACCTCAGGTAAATGGTCAGAGCGGTCGGATCGAC TTCCACTGGCTCATGCTGAATCCCAACGACACAGTTACTTTTTCATTCAATGGGGCATTC ATTGCGCCAGACAGGGCCTCCTTTCTAAGGGGTAAGTCGATGGGAATACAGTCTGGCGTG CAAGTAGATGCAAATTGCGAAGGGGACTGCTATCACTCTGGGGGCACGATCATCAGTAAC CTGCCTTTTCAGAACATCGACAGCCGAGCAGTAGGAAAATGCCCACGCTACGTGAAGCAG CGCTCACTGCTCTTAGCCACCGGGATGAAGAACGTCCCAGAAATTCCTAAAGGAAGGGGG CTGTTCGGCGCAATTGCTGGGTTTATTGAGAATGGATGGGAGGGTCTGATCGATGGCTGG TACGGTTTCAGACACCAGAACGCCCAAGGCGAAGGCACAGCCGCTGACTATAAGAGTACT CAAAGTGCAATTGACCAGATTACCGGCAAGTTGAATCGTCTGATTGAAAAGACAAATCAG CAGTTCGAACTGATAGATAATGAGTTTAATGAGGTTGAGAAACAGATAGGCAACGTGATT AACTGGACCAGGGACTCAATCACAGAAGTGTGGAGCTACAACGCGGAATTACTAGTGGCA ATGGAAAATCAGCATACTATCGACCTTGCAGATTCTGAAATGGACAAACTGTATGAAAGA GTGAAACGCCAGCTCCGTGAAAATGCCGAAGAGGACGGGACCGGTTGTTTTGAGATTTTC CATAAGTGTGACGACGATTGTATGGCAAGCATCCGTAATAATACATACGATCATTCGAAG TATCGCGAGGAGGCAATGCAGAACAGGATACAAATCGATCCTGTAAAACTGAGTAGTGGG TATAAAGATGTGATTTTGTGGTTCTCATTTGGCGCCTCTTGTTTCATCCTCCTCGCTATC GTGATGGGACTGGTGTTTATCTGCGTGAAGAATGGTAACATGCGGTGCACTATATGCATC 544 ATGAATACCCAGATCCTAGTGTTTGCCCTTATTGCCATCATACCGACAAACGCCGACAAG ATATGCCTAGGACATCACGCTGTCTCAAACGGTACCAAGGTTAACACGTTGACGGAGCGA GGAGTTGAGGTGGTGAACGCTACTGAGACCGTGGAACGCACTAACATTCCCCGCATTTGT AGTAAAGGCAAGAGAACTGTCGACCTGGGACAGTGCGGCCTCTTAGGGACCATCACAGGA CCCCCGCAGTGTGACCAGTTCCTCGAATTTTCTGCTGACCTGATCATTGAGCGGAGAGAG GGGAGCGATGTGTGCTACCCCGGAAAATTCGTAAATGAAGAAGCACTGCGACAGATTCTG CGGGAGAGTGGCGGAATTGATAAGGAAGCTATGGGGTTTACATACAGCGGGATCAGGACT AACGGAGCGACCAGCGCTTGCAGGCGGTCAGGAAGTTCTTTCTATGCAGAAATGAAGTGG CTGCTGTCCAACACGGACAATGCTGCTTTCCCCCAGATGACTAAATCCTACAAAAATACT CGAAAATCTCCCGCCCTTATTGTTTGGGGGATCCATCACAGCGTGTCGACCGCCGAACAG ACAAAGCTCTATGGAAGCGGTAACAAGCTTGTGACCGTTGGATCTTCCAATTATCAGCAG TCCTTTGTCCCCTCTCCTGGTGCCAGACCCCAGGTTAATGGCCTAAGCGGGCGCATCGAC TTTCATTGGCTCATGCTGAACCCTAATGATACCGTTACGTTTAGTTTTAATGGCGCCTTC ATTGCCCCTGACAGAGCATCTTTCCTGCGAGGGAAGTCAATGGGCATCCAGAGCGGTGTA CAGGTGGACGCCAATTGTGAGGGCGATTGTTATCACTCCGGGGGAACAATTATTAGTAAT CTGCCCTTCCAGAATATAGATTCGAGGGCGGTAGGTAAGTGTCCTCGCTACGTTAAACAA CGCTCTCTTCTTTTGGCCACTGGGATGAAGAACGTACCTGAAATACCTAAGGGTCGCGGG CTCTTTGGCGCGATCGCAGGCTTCATTGAAAACGGCTGGGAGGGTTTAATCAACGGGTGG TACGGTTTCCGACACCAGAACGCTCAGGGGGAAGGTACCGCTGCAGATTACAAGTCCACT CAATCAGCTATTGATCAGATCACGGGCAAGCTGAACAGGCTCATCGAAAAGACCAATCAG CAATTCGAACTCATCGATAACGAGTTCAACGAGGTGGAGAAGCAAATTGGAAATGTAATA AATTGGACGCGCGATTCTATTACAGAAGTGTGGTCCTACAACGCGGAACTCTTAGTGGCA ATGGAGAACCAGCATACTATTGACCTGGCTGACTCAGAAATGGATAAGCTGTACGAAAGG GTGAAAAGACAGTTGAGGGAAAATGCTGAGGAAGATGGGACGGGATGCTTTGAGATTTTC CATAAGTGCGATGATGACTGCATGGCAAGCATCCGTAACAACACATATGACCATTCTAAG TACCGGGAGGAAGCCATGCAAAATCGCATACAGATCGACCCTGTGAAGCTCAGTTCTGGC TACAAAGATGTGATCCTGTGGTTTTCGTTCGGAGCCAGCTGCTTTATCCTACTTGCAATA GTCATGGGTCTTGTGTTCATATGCGTAAAGAATGGCAACATGAGGTGTACCATCTGTATC 545 ATGAACACCCAGATTCTGGTGTTTGCCCTGATTGCTATAATTCCAACCAATGCGGACAAA ATCTGCCTGGGCCACCACGCCGTGTCGAACGGCACGAAAGTGAATACCTTAACGGAAAGA GGCGTTGAAGTTGTGAATGCAACAGAAACTGTAGAAAGAACTAATATTCCTAGAATCTGT TCTAAGGGGAAAAAAACGGTGGACTTAGGCCAGTGTGGTCTGCTAGGGACTATCACCGGC CCCCCTCAATGTGACCAGTTCCTGGAGTTCAGCGCCGACCTCATTATAGAAAGAAGAGAA GGATCAGACGTGTGCTACCCTGGCAAATTCGTAAACGAGGAGGCCCTCCGGCAGATCCTC CGCGAATCCGGTGGAATCGACAAGGAAGCCATGGGATTTACCTATTCTGGTATTCGGACC AACGGCGCCACGAGTGCTTGTCGGCGGTCAGGGTCTTCCTTTTACGCAGAGATGAAGTGG CTCCTGTCCAATACTGACAATGCCGCATTCCCTCAAATGACTAAGTCCTATAAAAATACC AGAAAATCTCCTGCACTTATCGTGTGGGGCATTCATCACTCTGTCAGTACTGCCGAGCAG ACCAAGCTATACGGGAGCGGTAACAAGCTTGTGACAGTAGGGTCATCCAACTATCAGCAA AGCTTTGTACCGTCCCCTGGGGCACGTCCCCAGGTGAACGGCCAGTCCGGGCGGATCGAC TTCCACTGGTTGATGCTGAATCCTAACGATACCGTGACCTTCTCTTTCAACGGGGCATTT ATCGCACCAGACAGGGCTTCCTTTCTGCGCGGAAAGTCCATGGGCATCCAGTCCGGCGTG CAGGTCGATGCAAACTGCGAGGGTGATTGCTACCATTCTGGGGGGACAATAATCTCTAAT CTGCCTTTTCAGAACATTGACAGTCGAGCGGTGGGCAAGTGTCCCAGGTACGTGAAACAA CGCTCCCTTCTGTTGGCAACAGGGATGAAGAACGTGCCTGAGATCCCGAAAGGCCGTGGA TTATTTGGCGCTATTGCTGGCTTCATTGAGAATGGATGGGAGGGCTTAATCGACGGTTGG TACGGCTTCCGGCATCAGAATGCACAGGGCGAAGGAACAGCTGCCGACTATAAATCCACC CAGTCCGCAATCGATCAGATAACCGGCAAGCTGAACCGGCTCATTGAGAAAACAAATCAG CAGTTCGAGCTCATAGACAATGAGTTTAACGAGGTAGAGAAACAGATTGGTAATGTCATT AACTGGACACGGGATAGCATCACGGAAGTTTGGAGCTATAATGCTGAGCTCTTGGTCGCT ATGGAGAACCAGCATACGATTGACTTGGCAGACTCTGAGATGGATAAGCTTTATGAGCGC GTGAAGAGGCAACTTAGAGAGAACGCTGAGGAGGACGGTACTGGGTGCTTCGAGATATTC CATAAGTGCGACGATGACTGCATGGCCAGCATTAGAAACAACACATATGATCACTCCAAG TATCGTGAAGAAGCCATGCAGAATCGGATTCAGATTGATCCAGTGAAGCTGTCCTCCGGC TACAAGGATGTGATCCTGTGGTTCTCGTTCGGTGCTAGCTGCTTCATATTGTTAGCTATC GTTATGGGCCTCGTGTTCATCTGCGTGAAGAACGGTAACATGCGTTGCACTATCTGCATA 546 ATGAACACTCAAATTCTGGTGTTCGCACTCATTGCCATCATACCAACTAACGCTGACAAG ATATGCTTGGGCCATCACGCCGTGAGCAATGGGACAAAGGTAAACACCCTCACAGAAAGA GGCGTCGAAGTGGTTAATGCTACAGAGACAGTCGAGAGGACAAACATCCCCCGTATTTGT TCCAAGGGTAAGAAAACTGTTGATCTGGGCCAGTGTGGGTTGTTAGGAACCATCACCGGA CCCCCGCAATGTGATCAATTCCTGGAATTTTCTGCGGATCTGATTATTGAGAGGCGCGAA GGCAGCGATGTGTGTTATCCCGGAAAGTTTGTTAACGAAGAAGCACTGCGGCAGATTCTG CGAGAATCCGGTGGCATCGACAAAGAGGCTATGGGCTTTACTTATTCCGGCATCAGGACG AATGGAGCCACCTCTGCCTGCCGCCGGTCAGGGAGTTCCTTCTATGCAGAGATGAAGTGG CTGCTCTCCAATACAGATAATGCCGCATTCCCTCAGATGACGAAATCTTATAAAAACACA CGGAAGAGTCCCGCACTGATCGTCTGGGGAATTCACCACTCCGTGAGCACTGCAGAGCAA ACCAAGCTGTACGGGTCAGGGAACAAGTTAGTGACAGTCGGAAGCTCTAATTATCAACAG TCGTTCGTGCCAAGTCCTGGGGCCCGACCGCAGGTGAATGGTCAGTCAGGGCGTATCGAT TTCCACTGGTTAATGCTGAATCCAAACGACACCGTGACCTTCTCCTTTAATGGCGCCTTT ATTGCACCCGATAGAGCTTCCTTTTTAAGAGGAAAATCCATGGGAATTCAAAGTGGTGTG CAGGTAGATGCGAATTGCGAGGGAGATTGTTATCACTCCGGTGGGACCATTATCTCCAAC CTCCCTTTCCAGAACATCGACTCGCGAGCTGTGGGCAAGTGCCCAAGATACGTTAAGCAG AGATCGCTTCTGTTGGCCACCGGAATGAAGAACGTTCCTGAAATTCCTAAGGGCCGCGGA TTATTCGGCGCCATTGCAGGCTTTATAGAAAACGGTTGGGAGGGCCTTATCGATGGATGG TATGGCTTCAGACACCAGAATGCACAAGGGGAGGGGACTGCCGCCGACTATAAGTCGACC CAGAGCGCAATTGATCAGATTACTGGGAAGCTTAATAGACTCATCGAGAAAACAAACCAA CAGTTCGAACTCATTGACAACGAGTTTAATGAGGTTGAGAAGCAGATCGGTAATGTCATC AACTGGACAAGAGACAGCATCACTGAGGTGTGGTCCTATAATGCTGAGCTGCTGGTAGCT ATGGAGAACCAACACACAATTGATCTCGCCGACTCAGAGATGGACAAGTTGTACGAGCGC GTCAAGAGGCAATTAAGAGAAAACGCCGAGGAGGATGGGACCGGCTGTTTTGAGATCTTC CATAAATGCGATGATGACTGTATGGCTAGCATCCGAAACAACACTTATGACCACTCCAAA TATCGGGAAGAAGCAATGCAGAATCGAATTCAAATTGACCCAGTTAAACTCAGTTCCGGA TATAAGGACGTTATCCTCTGGTTCAGCTTCGGAGCATCTTGCTTTATACTGCTGGCAATC GTTATGGGACTCGTGTTCATCTGTGTCAAGAACGGTAACATGAGATGTACTATCTGCATT 547 ATGAACACACAAATCTTGGTCTTTGCTCTCATTGCAATAATACCGACAAATGCCGATAAA ATCTGTCTAGGACACCACGCTGTATCCAATGGAACAAAGGTCAATACCTTGACAGAGCGC GGCGTAGAGGTGGTAAATGCCACAGAGACAGTCGAGCGAACAAATATTCCCCGCATATGT TCCAAAGGTAAAAAGACCGTTGACCTCGGGCAGTGCGGATTACTGGGAACAATCACGGGC CCCCCACAGTGTGACCAATTTCTGGAGTTCAGTGCCGATTTAATCATAGAGCGCAGGGAA GGTTCCGACGTCTGTTATCCTGGCAAGTTTGTAAACGAGGAGGCCTTACGGCAAATACTG AGGGAGTCAGGCGGCATCGAGAAGGAAGCCATGGGCTTCACCTATTCCGGAATTCGGGCG AACGGCGCAACCTCGGCCTGCCGACGGAGCGGAAGCTCATTTTACGCCGAGATGAAGTGG CTGCTTTCCAACACTGACAACGCAGCTTTCCCTCAAATGACAAAGTCGTATAAGAACACA AGAAAATCTCCTGCCCTCATTGTTTGGGGCATACACCATTCCGTGTCAACAGCAGAACAG ACAAAACTCTACGGCTCGGGTAACAAGCTCGTGACAGTCGGTTCCAGTAATTACCAGCAG TCCTTTGTACCTTCCCCCGGTGCACGGCCCCAGGTGAACGGCCTCTCTGGCAGGATTGAT TTCCACTGGCTGATGCTGAATCCTAACGATACAGTCACTTTTAGCTTTAATGGAGCTTTC ATTGCACCCGACCGCGCCAGCTTTTTGAGGGGAAAATCCATGGGGATCCAATCCGGAGTG CAGGTGGATGCTAACTGCGAAGGCGATTGTTATCATAGTGGGGGGACCATAATCAGTAAC CTCCCTTTTCAGAATATCGACTCCCGCGCAGTAGGAAAATGCCCTAGGTACGTGAAACAG CGCTCCTTACTGCTCGCCACGGGCATGAAGAATGTTCCTGAGATACCAAAAGGGCGGGGC CTGTTTGGGGCTATTGCGGGATTCATTGAAAACGGGTGGGAGGGGTTGATCGATGGCTGG TACGGGTTCAGGCACCAGAATGCCCAGGGTGAAGGAACAGCAGCCGACTACAAGTCTACG CAGTCTGCTATCGATCAGATTACCGGCAAGCTAAACCGCTTAATTGAAAAAACCAACCAA CAGTTCGAACTGATCGACAATGAGTTTAACGAAGTGGAAAAGCAGATAGGGAACGTGATT AATTGGACCAGAGACAGTATTACCGAGGTGTGGTCGTATAATGCCGAACTGTTGGTAGCT ATGGAGAACCAGCACACGATAGATCTGGCAGACAGTGAAATGGATAAGCTGTATGAGAGA GTAAAGCGGCAACTCCGGGAAAATGCAGAAGAGGATGGCACAGGATGCTTCGAGATATTC CATAAGTGTGATGACGATTGTATGGCCAGCATCAGAAACAATACCTACGACCACTCAAAA TACCGCGAAGAGGCCATGCAGAATAGGATTCAAATTGACCCAGTGAAGCTCTCCTCGGGA TACAAAGATGTGATCTTGTGGTTCAGCTTCGGCGCCTCCTGTTTTATCCTCCTGGCGATA GTGATGGGACTCGTCTTTATTTGCGTTAAGAACGGGAACATGAGGTGCACCATATGCATC 548 ATGAACACCCAGATCCTAGTGTTTGCACTTATCGCCATCATCCCGACTAATGCGGACAAG ATCTGCCTGGGCCATCACGCTGTGTCTAATGGAACCAAGGTGAATACGCTGACGGAACGA GGAGTGGAGGTGGTAAATGCTACGGAAACAGTCGAGAGAACCAACATCCCACGGATCTGC TCTAAGGGAAAAAAGACCGTTGATCTGGGCCAATGCGGTCTACTCGGTACCATTACCGGA CCACCACAATGCGACCAGTTTCTCGAATTCAGCGCCGACTTGATCATAGAAAGGCGCGAG GGATCGGATGTGTGCTACCCTGGCAAATTCGTGAATGAGGAGGCCCTCCGCCAGATCCTT AGAGAATCAGGTGGCATCGATAAGGAAGCTATGGGCTTCACATACTCGGGCATAAGAACA AATGGCGCTACCAGCGCCTGTCGACGCTCGGGCAGCTCCTTTTATGCCGAGATGAAGTGG TTGCTCAGTAACACAGATAACGCAGCCTTCCCACAGATGACAAAGTCTTACAAGAATACC CGTAAAAGCCCAGCCCTTATTGTGTGGGGAATACACCATAGCGTGAGCACGGCAGAGCAG ACGAAACTGTATGGTAGCGGGAACAAACTCGTTACGGTCGGGAGCTCAAACTACCAGCAG TCTTTTGTACCTTCACCCGGCGCTCGCCCACAGGTTAACGGTCAGTCGGGGAGAATCGAT TTCCACTGGCTGATGCTGAACCCAAATGACACCGTCACCTTCTCCTTCAACGGAGCCTTC ATTGCCCCAGATCGCGCCTCTTTTCTTAGAGGCAAGTCCATGGGCATCCAATCAGGCGTC CAGGTCGATGCCAATTGTGAAGGCGACTGTTATCATTCCGGAGGCACAATTATAAGCAAC CTGCCCTTCCAGAACATCGACAGTCGAGCTGTCGGTAAGTGCCCTCGTTACGTGAAGCAG CGGAGTCTCCTCTTAGCTACAGGAATGAAAAATGTCCCAGAGATCCCTAAAGGACGCGGT CTCTTTGGGGCCATAGCTGGATTCATCGAAAACGGCTGGGAAGGCCTGATCGACGGCTGG TACGGCTTCAGACACCAGAATGCACAAGGGGAAGGAACCGCTGCTGATTATAAGAGTACC CAGTCAGCTATCGACCAAATAACCGGTAAGCTTAACCGACTGATTGAGAAAACAAACCAG CAATTTGAGCTCATTGATAATGAGTTTAATGAGGTGGAAAAGCAGATTGGCAATGTCATT AACTGGACCCGCGACTCGATTACAGAAGTGTGGTCTTATAACGCGGAGTTACTTGTCGCC ATGGAAAATCAGCACACCATCGACTTGGCCGACTCTGAAATGGACAAACTGTACGAGCGA GTCAAGCGACAACTGAGGGAGAACGCCGAGGAAGACGGGACCGGTTGTTTTGAGATATTT CACAAATGCGACGATGACTGCATGGCCTCGATCAGGAACAATACTTACGACCACTCCAAG TACAGGGAAGAAGCGATGCAAAACAGGATACAGATAGATCCTGTTAAGCTCTCCAGTGGG TATAAAGACGTGATCCTGTGGTTCAGCTTCGGAGCATCCTGTTTTATCCTTTTGGCCATC GTAATGGGATTAGTCTTCATCTGCGTGAAGAATGGGAACATGCGGTGCACCATCTGTATA 549 ATGAATACCCAGATATTGGTATTTGCCCTGATAGCGATCATTCCAACTAACGCAGATAAG ATATGCCTCGGCCACCACGCTGTGTCGAATGGGACTAAGGTGAATACCCTGACTGAAAGA GGTGTCGAGGTGGTCAACGCTACCGAAACAGTGGAAAGGACCAACATACCGAGAATCTGC AGCAAAGGTAAAAAGACTGTAGACCTCGGCCAGTGCGGCCTTCTGGGGACCATTACTGGA CCTCCCCAATGCGATCAGTTCCTGGAGTTCTCTGCCGACCTCATCATTGAGCGGAGAGAG GGAAGCGATGTGTGCTACCCCGGCAAATTTGTGAATGAGGAGGCTCTGAGACAGATTTTG AGGGAGAGTGGCGGGATCGAAAAGGAGGCAATGGGGTTTACCTACTCAGGAATCAGGGCC AACGGAGCAACCTCTGCATGCAGAAGGTCCGGGTCCTCCTTCTACGCAGAGATGAAATGG CTGTTAAGCAATACGGATAATGCCGCCTTCCCTCAGATGACTAAGTCCTATAAAAATACC CGTAAGAGTCCAGCACTCATAGTCTGGGGCATTCACCATTCCGTCTCTACAGCAGAGCAG ACTAAACTCTATGGAAGCGGGAACAAACTCGTGACCGTCGGCTCGAGCAACTATCAACAA TCTTTCGTTCCATCTCCCGGAGCCAGACCCCAGGTGAACGGGCTATCGGGACGGATCGAC TTCCACTGGCTGATGTTAAACCCCAATGATACGGTCACCTTTAGCTTCAATGGTGCATTC ATCGCTCCAGACCGGGCCTCGTTTCTCAGAGGAAAATCTATGGGAATCCAGAGTGGTGTG CAGGTGGACGCCAACTGCGAGGGTGATTGTTATCATTCTGGGGGCACTATCATCTCAAAC CTCCCATTCCAGAACATAGATTCAAGAGCAGTTGGAAAGTGTCCAAGATATGTGAAGCAG CGCTCTCTGCTTTTGGCCACCGGCATGAAAAATGTTCCTGAGATACCGAAAGGACGGGGC CTATTTGGCGCGATCGCAGGATTCATCGAAAATGGATGGGAGGGACTGATCGACGGTTGG TATGGCTTCCGCCACCAGAATGCCCAGGGGGAAGGTACCGCAGCTGACTATAAATCAACG CAGTCCGCCATCGATCAGATAACTGGCAAACTGAATAGGCTAATAGAAAAGACTAACCAG CAGTTTGAGCTGATTGACAATGAATTCAACGAAGTGGAGAAGCAGATTGGCAACGTTATT AACTGGACCCGGGACTCCATCACGGAGGTGTGGTCTTACAACGCAGAGTTACTAGTAGCA ATGGAGAATCAGCACACTATAGACCTAGCCGATAGTGAAATGGACAAACTATATGAGAGA GTCAAACGCCAACTGCGGGAGAACGCCGAAGAAGATGGAACAGGATGTTTCGAGATTTTC CACAAATGTGATGATGATTGCATGGCGTCTATCCGCAATAATACTTACGATCATTCAAAG TACCGCGAAGAGGCCATGCAGAACCGAATCCAGATTGATCCCGTGAAGCTTTCCTCCGGA TACAAAGATGTAATCCTGTGGTTCTCATTCGGCGCTTCCTGTTTCATCTTACTGGCAATC GTCATGGGGCTGGTTTTCATTTGCGTCAAAAACGGCAATATGAGATGTACTATTTGCATC 550 ATGAACACCCAGATCCTGGTTTTTGCCTTGATCGCAATTATTCCTACCAATGCGGACAAA ATTTGCCTTGGGCACCACGCCGTTTCCAATGGCACAAAGGTCAACACTTTGACCGAACGG GGAGTGGAAGTGGTGAACGCTACAGAAACCGTTGAGCGGACTAACATTCCCAGGATCTGT AGTAAGGGCAAGCGCACCGTGGACCTGGGCCAGTGCGGATTGTTAGGCACCATCACCGGC CCACCCCAGTGCGACCAGTTCCTGGAATTTAGTGCAGATTTAATCATAGAACGAAGAGAG GGTTCTGATGTGTGTTACCCGGGGAAATTCGTGAACGAAGAGGCCCTCCGCCAGATTTTG AGAGAGAGCGGAGGCATAGATAAAGAAGCAATGGGCTTTACCTATAGCGGGATCCGGACT AATGGAGCTACCTCTGCATGTCGGCGTAGTGGAAGTTCTTTCTATGCTGAGATGAAATGG CTCCTTTCTAACACAGACAATGCTGCATTTCCACAAATGACAAAATCCTATAAAAATACT CGGAAATCCCCAGCCCTGATCGTTTGGGGAATCCACCATTCAGTTTCGACTGCAGAACAG ACTAAATTGTATGGGTCCGGGTCTAAGCTGGTAACAGTTGGAAGTTCCAATTACCAGCAA AGCTTCGTCCCCTCGCCAGGTGCACGCCCACAGGTGAACGGGCTAAGCGGGCGTATTGAT TTCCACTGGTTAATGCTGAATCCAAACGACACTGTCACGTTCAGCTTTAACGGAGCGTTC ATCGCTCCTGACCGCGCCAGTTTCCTGCGAGGTAAATCAATGGGCATCCAGTCAGGTGTT CAGGTAGATGCCAACTGTGAGGGGGATTGCTATCATTCTGGGGGGACTATTATTAGTAAC CTGCCCTTCCAGAATATAGATTCTCGGGCCGTCGGCAAGTGTCCAAGGTACGTTAAACAG CGCAGTCTGTTACTTGCCACTGGAATGAAGAACGTTCCCGAGATCCCAAAGGGCCGAGGT CTGTTCGGGGCCATCGCCGGCTTTATCGAGAATGGATGGGAAGGGTTGATTGATGGATGG TATGGTTTCCGTCACCAAAATGCCCAGGGAGAGGGGACAGCTGCTGACTATAAGTCCACC CAGAGTGCAATAGACCAAATCACAGGGAAACTGAATAGACTTATCGAAAAGACCAACCAG CAGTTTGAGTTGATTGATAACGAATTCAATGAAGTCGAGAAACAGATTGGGAATGTCATT AATTGGACACGAGACTCCATCACAGAGGTGTGGTCCTACAATGCCGAATTGTTGGTGGCC ATGGAGAATCAACATACTATCGATCTGGCAGACTCAGAAATGGACAAGCTGTATGAGCGA GTGAAGAGGCAGCTGAGAGAGAACGCCGAAGAAGATGGAACCGGGTGCTTTGAGATTTTT CATAAGTGTGACGACGATTGTATGGCAAGTATCCGCAATAATACCTACGACCACTCCAAG TATAGAGAGGAAGCCATGCAGAACCGGATTCAGATTGATCCAGTGAAACTCAGTTCCGGC TATAAAGACGTGATCCTGTGGTTTAGCTTCGGCGCCTCCTGTTTCATCCTGTTGGCCATT GTCATGGGGCTGGTCTTTATCTGTGTCAAGTCCCGAAACATGCGATGCACAATCTGCATC 551 ATGAACACTCAAATTCTAGTGTTCGCACTGATTGCCATTATCCCAACTAACGCCGACAAA ATCTGTTTGGGCCACCATGCTGTTAGCAACGGTACCAAAGTGAATACCCTGACCGAAAGA GGCGTTGAAGTAGTAAACGCCACTGAAACCGTTGAGAGGACAAACATTCCACGGATTTGT AGCAAAGGAAAGAAAACTGTCGATCTGGGGCAATGTGGACTGCTGGGCACCATCACTGGC CCTCCCCAGTGTGACCAGTTTCTGGAGTTTTCCGCAGATTTAATCATAGAGCGCAGAGAA GGAAGTGACGTGTGCTACCCTGGGAAATTCGTTAATGAAGAAGCCCTCCGGCAGATCCTA AGAGAATCTGGGGGTATCGAAAAGGAGGCAATGGGATTCACGTACTCGGGGATCCGTGCT AACGGAGCAACTTCCGCATGCCGGAGGTCAGGGTCATCTTTTTATGCTGAAATGAAATGG TTGCTGTCAAATACCGATAACGCCGCGTTCCCGCAAATGACAAAGAGCTACAAAAATACC CGCAAGAGTCCCGCGCTCATCGTGTGGGGCATCCATCATAGCGTGTCCACTGCTGAGCAG ACCAAACTTTATGGTAGTGGGAACAAGCTGGTCACGGTCGGATCAAGCAATTACCAGCAG TCCTTCGTACCAAGCCCGGGGGCCCGGCCCCAGGTGAACGGCCTGTCAGGACGCATCGAC TTTCACTGGTTGATGTTGAACCCGAATGATACAGTGACTTTTTCATTCAACGGCGCTTTT ATCGCACCAGACAGGGCCTCCTTTCTCCGCGGGAAGAGCATGGGCATCCAGAGTGGTGTG CAGGTTGACGCGAATTGCGAGGGAGACTGTTATCACTCAGGCGGAACAATTATCAGCAAT CTTCCTTTCCAAAACATTGATTCGAGAGCCGTCGGGAAGTGCCCCAGGTACGTCAAGCAG CGAAGTCTGCTTTTAGCTACAGGAATGAAGAACGTGCCCGAGATACCCAAAGGCAGGGGA CTGTTCGGCGCAATCGCTGGCTTTATTGAGAACGGATGGGAAGGTCTGATCGATGGCTGG TATGGATTTAGGCACCAGAACGCTCAGGGCGAGGGCACTGCAGCCGATTATAAGAGCACG CAGTCTGCCATAGACCAAATCACCGGGAAACTCAACAGGCTGATCGAGAAGACCAACCAG CAATTTGAGCTCATTGACAATGAATTTAATGAAGTGGAGAAGCAGATCGGCAATGTTATT AATTGGACACGAGACTCTATTACTGAAGTGTGGTCTTACAATGCCGAGCTGCTTGTTGCA ATGGAGAATCAGCATACAATCGATCTGGCCGATTCAGAGATGGACAAGCTGTACGAAAGG GTGAAACGGCAGCTACGGGAGAACGCTGAGGAGGATGGCACAGGGTGCTTTGAGATTTTC CATAAGTGCGACGACGATTGTATGGCGAGTATACGCAATAACACCTACGATCATTCAAAG TATCGCGAGGAAGCCATGCAGAACCGCATTCAGATCGATCCCGTGAAGTTGTCCTCTGGC TACAAAGACGTCATTCTGTGGTTCAGCTTTGGAGCATCCTGTTTCATCCTCCTGGCAATC GTGATGGGACTCGTGTTTATCTGCGTCAAAAACGGCAATATGAGGTGCACCATCTGTATT 552 ATGAATACACAGATCTTGGTTTTCGCTCTGATCGCCATCATACCGACCAATGCTGACAAA ATCTGTCTGGGTCACCATGCAGTGAGCAACGGTACCAAAGTCAATACATTGACCGAGCGT GGCGTCGAAGTTGTTAATGCCACAGAAACAGTCGAGCGAACCAATATTCCGAGAATTTGC TCCAAGGGGAAGAAGACCGTGGACCTAGGCCAGTGTGGACTGCTGGGTACAATTACTGGG CCACCACAGTGTGATCAGTTCCTGGAGTTCAGCGCAGATCTGATCATCGAACGGAGAGAG GGATCAGATGTATGCTATCCTGGTAAATTCGTAAACGAAGAGGCCCTGCGACAGATTCTA AGAAAAAGCGGAGGCATCGATAAGGAAGCTATGGGGTTCACATATTCAGGCATCAGAACT AATGGTGCCACTTCCACTTGCCGACGAAGCGGGAGTAGCTTCTACGCAGAAATGAAATGG CTTCTATCAAACACGGACAACGCGGCCTTTCCTCAGATGACCAAATCCTATAAGAACACC AGAAAAAGCCCCGCAATCATCGTATGGGGAATTCATCACTCTGTGAGTACCGCCGAGCAG ACAAAGCTTTACGGCTCCGGAAACAAGCTGGTGACCGTTGGGAGTAGCAATTACCAGCAG TCTTTCGTACCATCCCCCGGTGCGAGACCCCAAGTTAACGGCCTTTCAGGACGCATTGAT TTCCACTGGCTGATGTTGAATCCGAACGACACCGTGACGTTCTCCTTCAACGGGGCATTC ATTGCACCCGATAGAGCCTGTTTCCTCAGGGGAAAATCCATGGGCATACAGAGCGGGGTG CAGGTGGACGCCGACTGTGAGGGAGACTGCTACCACTCTGGTGGTACGATCATAAGCAAC CTCCCATTCCAGAATATCGATTCTAGGGCGGTGGGTAAATGTCCAAGATATGTGAAGCAG CGGTCTCTTCTGCTGGCCACCGGCATGAAAAACGTTCCTGAGATTCCCAAAGGCAGAGGG CTGTTCGGCGCAATCGCCGGCTTTATAGAAAACGGATGGGAGGGCCTGATCGATGGGTGG TACGGATTCAGACACCAGAATGCCCAGGGCGAAGGTACAGCTGCAGATTACAAAAGCACA CAGTCAGCCATTGACCAAATCACAGGCAAACTGAATCGCCTCATTGAGAAAACGAATCAG CAGTTCGAGCTCATTGATAACGAGTTCAACGAGGTCGAAAGACAAATTGGTAATGTGATC AACTGGACGAGGGACTCAATCACTGAGGTGTGGTCTTATAATGCAGAGCTGTTGGTGGCT ATGGAGAATCAACACACAATTGACCTGGCGGATTCTGAAATGGATAAACTGTACGAACGA GTCAAGCGTCAGCTGAGGGAGAACGCTGAGGAAGACGGGACTGGATGCTTCGAAATTTTC CATAAATGCGATGACGATTGCATGGCCTCTATCCGAAACAATACATACGATCATAGTAAG TACAGAGAAGAGGCCATGCAGAACAGAATCCAGATTGACCCGGTGAAACTGTCATCGGGA TACAAGGACGTCATCCTCTGGTTTTCTTTTGGTGCCTCTTGCTTCATATTACTGGCAATT GTTATGGGACTGGTCTTCATATGTGTTAAGAATGGTAACATGCGGTGTACAATATGCATC 553 ATGAACACTCAAATCCTCGTTTTCGCTCTGATTGCTATTATTCCTACTAATGCCGATAAG ATTTGTCTGGGCCACCATGCAGTTTCCAATGGAACCAAGGTTAACACCCTGACGGAGCGT GGTGTTGAGGTGGTTAATGCAACTGAAACTGTTGAGCGTACCAATATCCCTAGAATATGC AGTAAGGGGAAAAAAACTGTGGACCTCGGCCAATGTGGCCTGCTGGGCACCATCACAGGG CCGCCCCAATGTGATCAATTTTTAGAATTTAGCGCAGACCTGATTATCGAGCGCCGAGAA GGTAGCGACGTGTGCTACCCTGGCAAGTTTGTGAATGAGGAAGCCCTGAGACAAATTCTT AGGGAGTCAGGAGGCATCGACAAGGAAGCCATGGGCTTTACCTATAGCGGGATCAGAACA AATGGCGCAACTTCAGCCTGTAGGCGCTCGGGGTCCTCTTTCTACGCAGAGATGAAATGG CTGCTCAGCAATACAGACAATGCTGCTTTCCCTCAGATGACCAAGTCCTACAAAAATACC CGGAAGTCGCCCGCTTTGATCGTTTGGGGAATTCACCATTCTGTCAGCACGGCCGAGCAG ACTAAGCTATACGGGTCCGGTAACAAACTGGTGACAGTCGGCAGCAGCAATTACCAGCAG TCTTTCGTGCCCTCCCCAGGCGCAAGGCCCCAGGTAAATGGTCAGTCTGGACGCATAGAT TTTCACTGGCTCATGCTCAACCCCAATGACACAGTTACCTTTTCCTTCAATGGAGCCTTT ATCGCCCCGGATCGCGCCAGTTTTCTGCGGGGTAAATCCATGGGGATCCAGTCAGGGGTG CAGGTCGACGCTAACTGCGAGGGAGATTGTTACCACTCAGGAGGAACCATCATCAGCAAT TTGCCCTTCCAGAATATCGATTCTAGGGCAGTGGGCAAGTGTCCAAGGTACGTAAAGCAG CGATCCCTCCTGCTGGCCACCGGTATGAAAAATGTGCCAGAGATCCCTAAAGGTAGGGGG CTCTTCGGGGCTATCGCGGGCTTCATCGAGAATGGGTGGGAGGGACTCATCGATGGATGG TACGGCTTCAGACACCAGAACGCACAAGGCGAGGGGACAGCAGCTGATTATAAATCCACC CAGTCCGCTATCGACCAGATTACAGGGAAACTGAATCGGCTCATCGAGAAGACCAACCAG CAGTTCGAGCTGATTGACAATGAGTTCAATGAGGTTGAAAAGCAGATTGGCAACGTCATC AATTGGACTCGTGACAGCATCACCGAGGTTTGGTCCTACAACGCCGAGCTGCTCGTCGCC ATGGAGAATCAACACACTATAGACTTGGCCGACTCAGAAATGGATAAGCTATATGAGAGA GTTAAGCGACAGTTACGCGAGAACGCAGAAGAAGACGGTACCGGATGCTTTGAAATCTTT CACAAATGCGACGACGACTGTATGGCATCAATAAGAAACAACACCTACGATCACTCAAAG TACCGCGAGGAGGCCATGCAAAACCGGATCCAAATAGACCCCGTTAAGTTGTCCAGCGGG TATAAGGACGTGATTTTGTGGTTCTCTTTTGGGGCCTCCTGTTTCATTCTTCTGGCTATC GTGATGGGCCTGGTGTTCATATGTGTTAAGAATGGTAACATGAGATGTACTATCTGTATT 554 ATGAATACACAAATTCTGGTCTTCGCTCTGATCGCCATAATTCCCACCAACGCTGATAAG ATCTGTCTGGGCCACCACGCCGTCTCCAATGGTACTAAAGTAAACACTCTCACTGAGCGC GGCGTTGAAGTGGTCAATGCTACCGAGACTGTGGAGCGGACAAACATCCCAAGGATTTGC TCTAAGGGAAAGAGAACTGTGGACTTGGGCCAGTGTGGATTACTGGGCACAATTACAGGC CCTCCCCAGTGCGATCAGTTCTTGGAGTTTAGTGCCGACCTAATAATTGAACGCAGAGAG GGATCTGACGTGTGCTATCCAGGGAAATTTGTTAATGAAGAGGCACTCCGCCAGATTCTG CGAGAGTCCGGCGGGATCGACAAAGAGGCCATGGGATTCACGTATTCGGGCATCAGGACC AATGGCGCGACCTCCGCGTGTCGACGGAGCGGCAGTAGCTTTTATGCTGAGATGAAGTGG CTCCTCAGTAACACCGACAACGCTGCTTTCCCTCAGATGACCAAGTCATACAAGAATACC CGGAAATCCCCTGCACTTATCGTGTGGGGAATCCATCATTCCGTTAGTACCGCCGAGCAA ACTAAACTGTACGGGAGTGGCAACAAGCTTGTGACTGTGGGCTCATCGAATTATCAACAG TCGTTCGTCCCATCACCAGGCGCTAGGCCACAGGTTAATGGACTGTCGGGGCGCATCGAT TTTCACTGGTTAATGTTAAACCCTAATGACACCGTTACGTTTAGCTTCAATGGTGCCTTT ATCGCCCCCGACCGGGCCAGCTTCCTCCGTGGAAAGTCCATGGGAATTCAGTCAGGCGTA CAAGTGGATGCCAACTGTGAAGGCGATTGCTACCATTCTGGAGGAACCATTATTAGCAAC CTGCCCTTCCAGAACATTGATAGCAGGGCAGTAGGTAAATGTCCCCGGTATGTGAAACAA AGAAGCCTGCTGCTCGCCACTGGCATGAAAAACGTCCCTGAGATCCCGAAAGGTAGAGGC TTGTTCGGGGCAATTGCCGGGTTCATTGAAAACGGATGGGAAGGACTGATTGACGGATGG TATGGGTTCCGGCACCAAAATGCTCAGGGAGAAGGGACCGCAGCCGATTATAAGTCAACC CAAAGCGCCATTGACCAGATTACCGGAAAGCTTAACCGGCTCATCGAAAAGACAAATCAG CAGTTTGAGCTGATCGACAACGAATTTAATGAGGTGGAGAAGCAGATCGGAAACGTGATT AATTGGACTAGGGACAGCATCACCGAGGTCTGGTCTTATAACGCCGAACTGCTGGTAGCG ATGGAAAATCAACACACCATCGACCTGGCTGACTCAGAGATGGATAAGCTGTATGAAAGG GTCAAACGTCAGCTTCGTGAAAATGCTGAAGAGGATGGCACAGGTTGCTTCGAAATCTTC CATAAGTGTGATGATGATTGTATGGCTAGTATTAGGAACAACACATACGACCATTCCAAA TATCGGGAGGAAGCTATGCAAAACCGGATCCAAATCGACCCAGTTAAACTGTCTTCCGGC TACAAAGATGTTATTCTCTGGTTCAGTTTTGGTGCATCCTGCTTTATACTCCTTGCCATC GTAATGGGCCTGGTGTTTATCTGCGTCAAGAACGGAAACATGCGATGCACGATCTGTATC 555 ATGAACACTCAGATCCTCGTATTCGCCTTGATCGCTATTATTCCAACTAACGCCGATAAA ATCTGCCTTGGCCACCATGCCGTTAGCAACGGTACTAAAGTGAATACTCTTACAGAGAGG GGCGTCGAGGTCGTAAATGCCACTGAAACAGTTGAGCGAACAAACATTCCTCGAATTTGT TCTAAGGGAAAAAGAACAGTCGACCTCGGCCAGTGCGGATTGCTGGGAACCATTACGGGG CCTCCCCAGTGCGATCAGTTTCTGGAGTTTTCCGCCGACCTGATCATAGAGCGGCGCGAG GGTTCCGACGTGTGCTACCCAGGAAAATTTGTCAACGAAGAAGCACTACGACAGATCTTG AGAGAGAGCGGAGGGATTGACAAGGAAGCAATGGGATTCACTTATAGCGGCATCAGGACT AATGGTGCGACCTCTGCTTGCAGACGTTCCGGGTCATCCTTCTACGCAGAGATGAAGTGG TTACTAAGCAATACCGATAACGCAGCTTTTCCCCAGATGACCAAGTCCTACAAGAATACA CGGAAAAGCCCCGCTTTGATCGTTTGGGGTATCCATCACTCTGTGAGCACCGCAGAACAG ACAAAGTTGTACGGATCGGGAAGTAAGCTTGTCACCGTGGGCTCGTCCAACTACCAACAG TCTTTTGTACCTTCTCCAGGGGCTCGTCCACAAGTCAACGGCCTGTCTGGGAGAATCGAC TTTCACTGGCTCATGTTAAATCCCAATGACACAGTCACCTTCTCCTTTAATGGCGCCTTC ATTGCACCCGACCGTGCCTCATTCCTGAGAGGTAAGTCCATGGGAATTCAGAGCGGTGTC CAGGTCGACGCTAACTGCGAGGGGGACTGCTATCACTCCGGGGGGACAATTATCAGTAAT TTGCCCTTTCAGAATATTGATTCAAGAGCTGTTGGAAAGTGCCCACGCTACGTAAAGCAG AGAAGCCTCCTATTGGCCACAGGAATGAAGAACGTGCCGGAGATCCCCAAGGGTCGCGGT TTGTTTGGCGCCATCGCTGGCTTTATTGAAAACGGATGGGAGGGTTTGATTGATGGCTGG TATGGGTTCAGGCATCAGAACGCCCAGGGAGAAGGTACCGCAGCAGACTACAAGAGCACA CAGTCCGCCATTGACCAGATTACTGGTAAGCTGAACAGATTGATCGAAAAGACTAACCAG CAGTTTGAGCTGATTGACAATGAATTCAACGAAGTGGAAAAGCAGATCGGGAATGTGATC AATTGGACCCGGGATTCAATCACCGAGGTGTGGAGCTATAATGCCGAGCTGCTCGTAGCC ATGGAGAATCAACATACAATAGATCTCGCTGACTCCGAAATGGATAAGCTCTACGAGCGC GTAAAACGGCAGCTGCGCGAAAACGCTGAAGAAGATGGAACTGGATGCTTCGAGATCTTT CATAAGTGCGACGATGATTGTATGGCCTCCATTAGAAATAATACCTATGACCATAGCAAG TACAGGGAAGAGGCCATGCAAAATAGAATCCAGATCGATCCCGTCAAACTAAGTTCGGGG TATAAGGATGTGATCCTATGGTTTTCCTTTGGTGCTAGCTGTTTCATTCTGTTAGCCATC GTCATGGGGCTTGTGTTCATATGTGTGAAAAATGGTAACATGCGGTGCACAATTTGTATA 556 ATGAATACACAGATCTTAGTATTTGCGCTAATCGCTATTATCCCTACCAATGCTGATAAG ATCTGTCTGGGCCACCACGCCGTTTCCAATGGCACTAAAGTGAACACTCTCACTGAGCGC GGCGTCGAGGTGGTCAACGCCACCGAGACAGTTGAGAGAACAAACATACCTCGCATCTGT AGTAAAGGCAAGAAGACTGTCGATCTGGGCCAGTGTGGGCTGCTGGGAACGATAACCGGT CCCCCTCAGTGTGATCAGTTTCTGGAATTCTCTGCAGACCTGATTATCGAAAGACGAGAA GGGAGCGACGTGTGTTACCCCGGAAAGTTTGTTAATGAGGAAGCACTGCGCCAGATCCTT CGGGAATCTGGGGGCATCGATAAGGAAGCGATGGGCTTCACTTATAGTGGGATTCGCACC AACGGGGCTACGTCCGCTTGCCGGCGGAGCGGTTCGTCTTTTTACGCGGAAATGAAGTGG CTGCTCAGCAATACCGATAACGCCGCCTTCCCGCAGATGACAAAAAGCTATAAGAATACC CGGAAAAGTCCGGCACTCATAGTGTGGGGGATCCACCATAGCGTTAGCACGGCGGAGCAG ACAAAGCTCTATGGGAGTGGAAATAAGCTGGTGACCGTCGGCTCTTCAAATTACCAGCAA TCATTTGTGCCCTCTCCCGGCGCCCGTCCTCAAGTGAACGGACAGTCAGGAAGGATTGAC TTCCACTGGCTCATGTTGAACCCTAATGACACAGTGACATTTTCGTTTAACGGAGCATTC ATCGCCCCTGACAGAGCTAGTTTCCTCAGAGGGAAGAGTATGGGGATCCAGAGCGGGGTA CAGGTGGATGCAAACTGTGAGGGGGACTGCTATCATTCTGGTGGGACCATCATTTCGAAC CTGCCATTCCAGAACATTGACTCTCGCGCTGTTGGCAAATGTCCTAGGTACGTTAAGCAA AGATCATTGCTGCTCGCAACGGGCATGAAAAACGTGCCGGAAATCCCTAAAGGTCGGGGT CTCTTCGGCGCCATCGCCGGATTCATTGAGAATGGCTGGGAGGGACTCATCGACGGGTGG TATGGGTTCCGGCATCAGAACGCACAGGGCGAGGGGACTGCCGCTGACTACAAATCGACC CAGTCCGCTATTGACCAGATCACCGGCAAACTCAACCGGCTGATCGAGAAGACTAACCAA CAGTTTGAACTCATCGATAATGAGTTCAACGAGGTAGAAAAACAAATTGGAAACGTGATC AATTGGACACGCGATTCTATTACTGAGGTCTGGAGTTATAACGCAGAGCTGCTGGTGGCT ATGGAAAACCAGCACACCATTGATCTAGCTGACTCGGAAATGGATAAGCTGTACGAAAGG GTGAAACGCCAGCTACGCGAAAATGCCGAGGAAGACGGTACAGGATGCTTCGAGATATTC CACAAGTGCGACGACGACTGCATGGCCAGCATCCGCAATAACACATATGACCATTCTAAA TACCGGGAGGAAGCCATGCAGAATCGAATCCAGATCGACCCTGTCAAATTAAGCAGTGGG TACAAGGACGTGATCCTGTGGTTTAGCTTCGGAGCTAGTTGTTTTATATTACTCGCCATC GTTATGGGATTGGTATTTATCTGCGTCAAGAATGGAAACATGCGCTGCACTATCTGCATC 557 ATGAACACCCAGATACTCGTCTTTGCCCTCATTGCCATAATCCCGACTAATGCGGATAAG ATTTGTCTAGGGCATCACGCTGTATCAAACGGCACGAAAGTCAACACCTTGACCGAAAGG GGCGTAGAGGTGGTAAACGCTACAGAAACAGTCGAGCGGACAAATATCCCAAGGATTTGC AGCAAGGGTAAAAAGACTGTAGACTTAGGACAGTGCGGCTTACTCGGCACAATCACAGGC CCCCCCCAATGTGATCAGTTCCTTGAATTCAGTGCAGATCTGATAATCGAAAGGAGGGAG GGATCTGACGTGTGTTACCCAGGCAAATTCGTCAACGAGGAAGCACTCAGACAGATCTTA AGAAAGTCCGGCGGGATAGACAAAGAAGCTATGGGTTTTACGTACAGTGGGATAAGAACC AATGGCGCCACTAGCACCTGTAGGAGGAGTGGGTCGTCCTTCTATGCTGAAATGAAGTGG CTGCTGTCCAATACTGACAATGCAGCCTTTCCTCAGATGACAAAGAGCTACAAGAATACA AGGAAAAGCCCGGCAATTATAGTATGGGGAATCCACCATTCAGTCAGCACCGCTGAACAA ACTAAGCTGTATGGCTCCGGCAATAAGCTCGTCACAGTGGGGAGCTCAAATTATCAGCAG TCATTCGTGCCAAGCCCAGGGGCGCGGCCGCAAGTTAACGGCCTCTCCGGAAGAATTGAT TTTCATTGGTTAATGCTTAATCCTAACGACACGGTTACCTTCAGCTTTAACGGCGCTTTC ATCGCTCCCGACAGGGCTTGTTTTCTCCGCGGCAAGTCTATGGGAATCCAGTCCGGGGTG CAGGTCGACGCGGATTGTGAAGGAGACTGCTACCACAGTGGGGGCACTATAATCTCAAAT CTGCCATTCCAGAATATCGACAGTCGCGCCGTGGGGAAGTGTCCGAGATACGTTAAGCAA CGATCACTGCTACTGGCCACCGGTATGAAAAATGTGCCAGAGATTCCCAAAGGGAGAGGC CTGTTTGGTGCCATCGCCGGGTTTATCGAGAACGGGTGGGAAGGCTTGATTGACGGCTGG TACGGATTTCGGCACCAAAACGCCCAAGGGGAAGGTACCGCTGCCGATTACAAGAGCACC CAAAGTGCCATTGACCAGATTACGGGGAAACTGAACAGACTGATCGAGAAAACGAATCAA CAATTCGAACTGATAGATAACGAATTTAACGAAGTCGAGCGACAGATCGGGAATGTGATC AACTGGACTAGGGATTCTATTACCGAGGTATGGAGCTATAATGCTGAGCTTCTTGTGGCA ATGGAAAATCAACACACAATAGATTTAGCGGATAGTGAGATGGACAAGCTCTACGAACGG GTAAAAAGACAGTTGAGAGAGAATGCCGAGGAGGACGGGACAGGCTGTTTTGAAATCTTC CATAAGTGTGACGATGATTGTATGGCGAGCATCCGAAACAATACTTACGATCACAGCAAA TACCGTGAGGAGGCGATGCAGAATAGAATCCAGATAGATCCGGTTAAACTGTCCAGCGGG TACAAGGATGTGATCCTGTGGTTCTCATTCGGCGCTTCATGTTTCATTTTGCTGGCAATT GTGATGGGACTCGTGTTCATATGTGTGAAAAACGGCAATATGCGCTGCACTATTTGCATC 558 ATGAATACACAGATCCTAGTGTTCGCACTCATAGCTATAATCCCTACAAATGCCGACAAG ATATGTCTTGGCCACCACGCTGTGTCAAACGGGACAAAAGTTAACACCTTGACAGAGCGG GGCGTCGAGGTCGTTAACGCCACCGAGACTGTGGAAAGAACAAATATACCCCGGATTTGT TCAAAAGGGAAGAGAACTGTCGACCTGGGGCAGTGCGGACTCCTGGGGACTATCACTGGA CCTCCACAATGCGACCAGTTCCTCGAGTTCTCTGCCGATCTCATCATTGAGAGGCGAGAG GGGTCCGATGTGTGTTACCCAGGGAAATTTGTGAATGAGGAAGCCCTTCGGCAGATACTT CGTGAAAGCGGGGGCATCGATAAAGAGGCCATGGGTTTTACGTATTCTGGAATTCGCACC AACGGGGCCACAAGTGCATGTCGGAGGAGCGGATCATCATTCTATGCAGAGATGAAATGG CTGCTTTCTAACACCGATAATGCCGCTTTCCCGCAGATGACAAAAAGTTATAAAAATACC AGGAAATCCCCCGCTCTAATTGTGTGGGGGATTCATCACAGCGTTTCCACTGCCGAACAG ACTAAGCTGTACGGTTCGGGCAGCAAGCTGGTGACAGTGGGTTCATCAAACTACCAACAG TCCTTCGTGCCTTCTCCAGGCGCGCGGCCGCAGGTTAACGGACTCTCTGGCAGAATCGAC TTTCATTGGTTGATGCTGAATCCCAACGACACCGTCACCTTCTCCTTTAACGGTGCATTT ATCGCCCCAGATCGTGCTTCATTTCTACGCGGCAAAAGCATGGGGATTCAGTCCGGCGTC CAGGTAGATGCAAACTGTGAGGGCGACTGTTACCACTCAGGCGGAACAATTATTAGCAAC CTGCCATTTCAGAATATTGACTCTCGCGCCGTGGGGAAATGCCCAAGATATGTCAAGCAG CGGAGCCTGCTCCTGGCCACTGGGATGAAGAATGTGCCAGAAATACCAAAGGGTAGAGGT CTGTTCGGCGCCATCGCTGGCTTTATAGAGAATGGATGGGAGGGACTGATCGATGGCTGG TACGGATTCAGACATCAAAACGCCCAAGGTGAAGGAACCGCTGCCGATTACAAGTCTACC CAAAGTGCTATAGATCAGATAACCGGCAAGCTTAATAGGCTCATTGAGAAAACAAATCAG CAGTTCGAGCTGATCGACAACGAGTTCAACGAGGTGGAGAAGCAGATTGGAAACGTGATT AATTGGACGCGCGATAGCATCACAGAGGTGTGGTCCTATAACGCAGAGCTGCTGGTGGCT ATGGAGAACCAGCACACTATCGATCTGGCCGACTCCGAAATGGACAAGCTGTACGAGAGG GTGAAGCGGCAGTTGCGAGAGAATGCCGAGGAGGACGGGACAGGCTGCTTTGAGATCTTT CACAAGTGCGACGATGATTGTATGGCTTCAATCCGCAATAACACATACGATCATTCCAAA TACAGGGAGGAAGCTATGCAGAACCGAATCCAGATAGATCCAGTGAAGCTCTCTAGTGGC TACAAGGACGTGATTCTGTGGTTCAGTTTCGGTGCTAGCTGTTTTATTCTGCTTGCAATA GTAATGGGGTTGGTGTTTATCTGTGTTAAGTCACGGAACATGCGCTGCACCATATGCATC 559 ATGAACACACAGATCCTAGTTTTCGCGCTGATCGCAATCATACCTACAAATGCTGACAAG ATTTGCCTAGGACATCACGCCGTGTCTAATGGAACCAAAGTAAACACTCTGACTGAGCGC GGGGTAGAGGTCGTGAATGCAACAGAAACGGTAGAGCGGACAAATATCCCTAGGATATGC AGTAAAGGCAAGCGTACAGTAGATCTCGGCCAGTGTGGCCTACTCGGAACAATCACCGGT CCTCCCCAGTGCGACCAGTTCCTTGAATTCAGTGCTGATCTGATCATTGAAAGGCGGGAG GGGTCCGATGTATGTTACCCTGGGAAGTTTGTCAATGAAGAGGCACTGCGCCAAATCCTG AGAGAGTCAGGAGGCATAGACAAAGAGGCTATGGGATTTACATACAGTGGGATAAGAACT AACGGCGCGACCAGCGCCTGCAGGAGGTCCGGGTCGTCTTTCTATGCCGAAATGAAATGG CTCCTTTCTAATACAGATAACGCAGCCTTTCCCCAGATCACTAAATCATACAAGAATACT AGGAAGTCACCCGCACTCATCGTTTGGGGCATACATCACTCGGTCAGCACCGCCGAACAG ACTAAATTATACGGTTCAGGGAACAAGCTCGTAACCGTGGGCTCGTCTAACTATCAACAG AGTTTCGTTCCGTCCCCCGGGGCGAGACCGCAGGTGAATGGCCTCTCCGGGCGAATCGAT TTTCATTGGCTGATGCTGAACCCCAACGATACCGTAACCTTTTCGTTCAACGGGGCTTTC ATCGCTCCGGATAGAGCATCATTTCTGCGCGGGAAGTCCATGGGCATTCAGAGCGGTGTT CAAGTCGACGCCAACTGTGAGGGAGACTGTTATCACAGCGGGGGGACCATCATCAGCAAC CTCCCGTTTCAGAATATTGACTCAAGGGCGGTCGGAAAGTGTCCACGTTACGTCAAGCAG CGGAGTCTCCTGTTAGCGACAGGCATGAAGAATGTCCCTGAAATTCCTAAAGGCCGGGGC CTATTTGGTGCCATCGCCGGTTTCATCGAGAACGGGTGGGAAGGTCTGATCGATGGTTGG TATGGCTTCCGCCACCAGAATGCGCAAGGGGAAGGAACCGCGGCGGACTACAAAAGTACT CAGTCCGCAATCGATCAGATCACAGGTAAGTTGAATAGGCTTATCGAGAAGACAAACCAG CAGTTTGAGCTTATAGACAACGAATTCAATGAGGTGGAAAAGCAAATTGGAAATGTAATC AATTGGACCAGGGATAGCATCACCGAAGTGTGGAGCTACAATGCCGAGCTGTTGGTGGCA ATGGAGAACCAACATACAATCGACCTAGCCGATAGTGAGATGGACAAGCTGTATGAGCGG GTGAAGCGGCAGCTGAGGGAAAATGCGGAGGAAGACGGAACTGGGTGTTTCGAGATTTTC CACAAGTGTGATGACGATTGTATGGCCTCAATTCGGAACAACACATACGATCATTCCAAG TATCGAGAAGAGGCCATGCAAAACCGGATTCAGATTGACCCCGTCAAGTTATCCTCCGGG TACAAGGACGTTATTCTCTGGTTTAGCTTTGGAGCCAGTTGCTTCATTCTGTTGGCAATT GTGATGGGTCTTGTATTCATCTGTGTGAAAAATGGGAATATGCGCTGCACCATCTGTATC 560 ATGAACACGCAAATCTTGGTGTTCGCACTGATCGCCATTATTCCAACCAATGCTGACAAG ATTTGCCTTGGTCACCACGCGGTTAGCAACGGGACCAAAGTGAACACCCTGACCGAGCGA GGGGTGGAGGTAGTGAACGCAACCGAGACAGTGGAGAGAACTAATATACCCCGGATCTGT AGCAAGGGTAAGAGAACGGTGGATCTTGGGCAGTGTGGCTTGTTGGGGACTATCACAGGC CCTCCTCAGTGCGACCAGTTCTTGGAATTTTCTGCCGACCTTATCATTGAGCGCAGAGAG GGGTCAGATGTCTGTTATCCTGGAAAATTTGTGAACGAAGAGGCTCTTCGGCAGATACTG CGCGAATCAGGCGGCATTGACAAAGAAGCCATGGGGTTTACCTATAGCGGAATCAGGACT AACGGCGCCACCTCCGCCTGCAGGAGGAGTGGGAGCAGCTTCTACGCTGAAATGAAGTGG TTGCTCTCTAACACAGACAATGCTGCATTCCCTCAGATTACCAAGAGTTATAAGAACACA CGCAAATCTCCCGCGCTGATCGTGTGGGGCATTCATCACAGCGTTAGCACGGCCGAGCAG ACAAAACTGTACGGCTCGGGAAATAAACTTGTGACGGTTGGCAGCAGCAACTATCAGCAG TCCTTCGTTCCTTCTCCAGGCGCGCGCCCCCAGGTGAATGGGTTGTCTGGGAGAATCGAC TTTCACTGGCTAATGCTTAATCCTAACGACACGGTGACTTTCTCATTTAACGGAGCTTTC ATCGCACCAGACCGCGCATCCTTTCTGAGAGGGAAATCGATGGGCATCCAATCCGGGGTG CAGGTCGATGCGAACTGCGAGGGTGATTGTTATCACTCCGGGGGCACCATAATCAGCAAC CTGCCTTTCCAGAATATCGACTCCCGGGCAGTAGGAAAGTGCCCACGATATGTGAAGCAG AGGAGCTTGCTGCTGGCTACAGGCATGAAGAATGTCCCAGAAATCCCCAAGGGGAGAGGT CTATTTGGGGCCATCGCTGGCTTTATAGAGAACGGGTGGGAAGGTCTGATTGACGGGTGG TACGGCTTTAGGCACCAGAACGCCCAGGGCGAAGGAACAGCTGCCGACTATAAATCTACA CAGAGCGCCATTGATCAGATAACTGGCAAGTTAAACCGGCTCATCGAGAAGACTAATCAG CAATTTGAGCTTATCGATAACGAATTCAATGAAGTAGAGAAACAAATCGGGAATGTGATC AACTGGACTCGAGATTCAATAACGGAGGTATGGTCCTACAACGCCGAACTGCTCGTTGCT ATGGAGAACCAGCACACCATCGATCTGGCAGACAGCGAGATGGATAAGCTCTACGAGAGA GTCAAGCGACAGTTACGTGAAAATGCCGAAGAAGATGGAACCGGTTGCTTTGAGATATTT CATAAATGCGATGATGATTGCATGGCTTCGATTCGGAATAACACATATGACCACAGCAAG TACAGGGAAGAAGCGATGCAAAACCGCATTCAGATCGACCCAGTCAAACTAAGCTCTGGA TACAAAGACGTTATACTGTGGTTCTCCTTTGGAGCCAGCTGCTTCATCCTGCTCGCCATA GTGATGGGACTGGTGTTTATCTGCGTGAAAAACGGAAACATGAGGTGTACCATTTGTATC 561 ATGAACACACAGATTCTCGTCTTCGCACTCATTGCCATCATCCCTACAAACGCGGACAAA ATTTGCCTTGGGCACCACGCCGTGAGCAACGGCACAAAAGTCAACACATTGACAGAGCGA GGCGTAGAGGTCGTTAATGCCACCGAAACGGTAGAAAGGACGAACATTCCTAGGATATGT AGTAAAGGAAAGCGTACTGTAGATTTAGGACAGTGTGGCTTGCTGGGAACTATCACAGGA CCCCCACAATGCGACCAGTTCCTAGAGTTTAGCGCCGATCTGATAATTGAACGTAGGGAG GGAAGCGACGTATGCTACCCAGGGAAATTTGTGAAGGAGGAGGCCCTCCGACAGATTCTG AGAGAGTCCGGGGGAATCGACAAGGAAGCCATGGGATTCACCTATTCGGGCATAAGAACC AACGGCGCAACATCCGCTTGCCGGAGGTCCGGGAGTAGTTTTTATGCTGAGATGAAGTGG CTGCTTTCCAACACCGATAACGCCGCCTTTCCTCAGATGACGAAATCCTATAAGAATACA AGAAAAAGCCCGGCACTCATCGTGTGGGGCATCCATCACAGCGTCTCCACGGCAGAGCAG ACTAAACTCTACGGATCTGGAAATAAACTGGTAACAGTGGGGTCAAGTAACTACCAACAG TCGTTCGTGCCATCCCCTGGCGCTCGGCCTCAGGTTAACGGGCTGTCCGGTAGGATTGAT TTCCATTGGCTGATGTTAAACCCAAACGACACCGTGACCTTCAGTTTTAACGGCGCTTTT ATTGCTCCCGACAGGGCAAGTTTCTTGAGGGGCAAGAGCATGGGAATCCAGTCTGGTGTG CAGGTCGATGCCAACTGTGAGGGAGATTGTTATCATAGCGGAGGTACGATTATCTCTAAT CTACCTTTTCAAAATATCGACTCCAGGGCGGTCGGGAAATGTCCTCGCTACGTCAAGCAG AGGTCACTGCTTCTGGCAACCGGAATGAAGAACGTGCCCGAAATCCCAAAGGGCAGAGGT CTGTTTGGCGCTATAGCCGGGTTCATTGAGAACGGATGGGAGGGTTTAATAGACGGGTGG TATGGATTCCGCCACCAAAATGCCCAGGGGGAAGGGACAGCTGCCGATTACAAGTCAACA CAGAGCGCGATCGATCAGATCACAGGAAAGTTGAACAGGTTGATAGAGAAAACAAATCAA CAGTTTGAGCTGATCGATAATGAGTTCAATGAGGTCGAGAAGCAAATTGGGAACGTAATA AATTGGACACGAGATTCCATAACTGAAGTGTGGTCTTACAATGCTGAACTGCTCGTGGCG ATGGAAAACCAACACACGATTGATTTGGCCGATTCCGAGATGGATAAACTGTATGAACGT GTGAAGCGTCAACTTCGTGAAAATGCCGAAGAGGACGGTACCGGATGCTTCGAGATCTTC CACAAGTGTGATGATGATTGCATGGCCAGTATCAGGAATAACACATATGACCATTCCAAA TACCGCGAAGAGGCCATGCAGAATCGTATTCAGATTGACCCCGTTAAGCTGAGTTCCGGT TACAAAGATGTCATTCTCTGGTTTTCTTTTGGCGCCTCATGTTTCATTCTGCTAGCCATT GTGATGGGGCTTGTCTTTATCTGTGTCAAGAACGGTAACATGAGGTGTACCATCTGTATC 562 ATGAATACCCAGATTCTGGTGTTCGCGTTAATAGCCATTATCCCAACTAACGCTGATAAG ATATGTCTGGGCCATCACGCTGTGAGCAATGGAACTAAGGTGAACACTCTGACCGAGAGG GGTGTGGAGGTAGTGAATGCTACCGAGACAGTAGAGCGGACTAACATTCCCAGGATTTGC TCTAAGGGCAAGCGCACCGTCGACCTGGGACAGTGCGGGTTGCTAGGTACGATAACTGGT CCACCACAATGTGATCAATTCTTGGAATTTTCTGCTGACCTCATTATAGAGAGGAGGGAG GGCTCCGATGTGTGCTACCCCGGGAAATTCGTCAACGAAGAAGCACTGCGTCAGATTTTG AGAGAATCGGGGGGTATTGACAAGGAGGCCATGGGTTTTACCTACTCCGGCATTCGTACT AACGGAGCCACCAGTGCCTGCAGGCGGAGCGGGAGTAGCTTCTACGCTGAGATGAAATGG CTTCTAAGCAACACTGATAACGCCGCTTTCCCCCAGATGACTAAATCTTACAAAAACACA CGGAAGAGTCCCGCTCTGATAGTATGGGGAATACACCATTCAGTCTCTACAGCCGAGCAG ACTAAGCTTTATGGAAGCGGGAACAAACTGGTGACCGTCGGTTCATCTAATTACCAGCAG TCTTTCGTGCCCTCTCCTGGGGCCAGGCCCCAGGTGAATGGGCTGTCTGGCCGCATTGAT TTCCACTGGTTAATGCTGAATCCCAATGATACCGTGACCTTTTCTTTCAATGGCGCTTTC ATTGCTCCTGATAGAGCCTCATTTCTGAGAGGGAAGTCGATGGGGATACAGTCTGGGGTC CAGGTCGACGCTAATTGCGAAGGCGATTGCTACCACTCTGGGGGGACAATTATAAGTAAT TTGCCGTTCCAGAATATCGATAGTAGAGCTGTGGGGAAATGCCCCCGCTACGTAAAGCAG CGTTCCCTTTTGCTTGCCACAGGTATGAAAAACGTGCCCGAAATTCCAAAAGGAAGAGGA CTATTTGGTGCCATTGCGGGGTTCATCGAAAACGGATGGGAGGGCCTGATCGATGGGTGG TACGGCTTCAGACATCAAAATGCTCAGGGGGAAGGAACTGCAGCGGACTATAAATCTACC CAGTCTGCCATCGATCAGATCACTGGCAAACTAAATCGACTTATCGAGAAAACAAACCAG CAGTTTGAGCTTATCGATAACGAGTTCAACGAGGTAGAAAAGCAGATTGGAAACGTCATT AACTGGACTCGGGATTCAATCACAGAAGTATGGAGTTACAACGCTGAGCTTTTAGTGGCC ATGGAAAATCAGCATACGATTGATCTCGCCGACTCCGAGATGGATAAGCTGTACGAACGT GTGAAGCGCCAGCTCAGAGAGAATGCAGAGGAGGACGGGACTGGCTGCTTCGAGATCTTT CATAAATGTGACGATGACTGCATGGCAAGCATTCGAAATAACACATACGATCATAGTAAG TATCGGGAGGAGGCTATGCAAAATCGGATTCAAATTGATCCGGTGAAGCTGTCGAGTGGC TACAAGGATGTGATTTTATGGTTTTCATTCGGGGCCTCCTGCTTCATCCTACTGGCCATA GTGATGGGCCTGGTGTTTATCTGCGTGAAAAATGGTAATATGCGGTGCACCATCTGCATC 563 ATGAATACTCAAATTTTAGTTTTCGCTCTTATTGCCATCATTCCAACTAACGCTGATAAA ATCTGCCTGGGCCACCACGCCGTCAGCAATGGGACCAAGGTAAACACACTCACCGAACGC GGCGTGGAAGTAGTGAATGCGACCGAAACTGTTGAGCGCACCAACATTCCACGAATATGT TCCAAGGGTAAGAAAACCGTGGATCTGGGGCAATGTGGCCTTCTGGGGACGATAACAGGA CCACCCCAGTGTGACCAGTTTCTGGAGTTTTCCGCAGACCTGATCATCGAACGTAGGGAG GGAAGCGACGTCTGTTATCCCGGCAAGTTCGTTAATGAGGAGGCCCTTCGACAAATCCTG CGCGAAAGCGGTGGGATAGACAAAGAAGCCATGGGCTTCACATACAGCGGGATCAGAACC AACGGCGCCACAAGTGCCTGCAGGCGATCTGGCTCGTCCTTCTACGCGGAGATGAAGTGG CTGCTGTCAAACACCGACAATGCCGCTTTTCCCCAGATGACAAAAAGCTACAAAAACACC CGAAAAAGCCCTGCATTAATAGTCTGGGGCATCCACCACAGCGTGTCTACCGCCGAACAA ACGAAGCTGTATGGTTCCGGAAACAAACTAGTGACGGTGGGCTCATCAAATTATCAGCAG TCCTTCGTGCCTTCCCCAGGGGCCAGGCCTCAGGTGAATGGACAATCCGGGCGAATTGAT TTTCATTGGCTCATGTTGAACCCCAACGACACTGTAACGTTTTCTTTCAACGGTGCGTTT ATCGCTCCAGATAGGGCCTCCTTCCTCCGAGGAAAAAGTATGGGTATCCAGAGTGGCGTG CAGGTGGATGCCAATTGCGAGGGTGACTGCTACCACTCTGGCGGTACAATTATCTCTAAT CTGCCCTTCCAGAACATAGACAGCCGTGCGGTCGGGAAGTGCCCCCGCTACGTTAAGCAA CGGTCTTTATTGCTTGCCACTGGTATGAAGAACGTGCCAGAGATACCAAAAGGGAGAGGG CTCTTTGGCGCCATCGCTGGATTTATAGAGAACGGGTGGGAGGGCCTGATTGACGGGTGG TACGGATTCCGCCATCAGAACGCCCAAGGTGAAGGCACCGCCGCCGACTACAAGAGCACC CAGAGCGCCATTGATCAGATCACGGGAAAACTGAATAGGCTGATTGAAAAGACAAATCAG CAGTTCGAGCTGATAGACAACGAATTTAACGAAGTAGAAAAACAAATCGGCAACGTGATC AACTGGACAAGAGACTCCATCACTGAAGTGTGGAGCTATAATGCCGAGTTACTCGTGGCA ATGGAGAATCAGCATACTATTGATCTGGCCGATTCGGAAATGGACAAGCTGTACGAACGC GTCAAGCGGCAACTGCGGGAGAATGCCGAGGAGGACGGTACCGGTTGTTTCGAGATTTTT CATAAATGTGATGACGACTGCATGGCCTCAATTAGAAACAACACATATGATCACAGCAAG TATCGGGAAGAAGCTATGCAAAACCGGATTCAGATCGACCCAGTTAAGCTGAGTAGCGGG TATAAGGACGTAATCCTCTGGTTTTCTTTCGGCGCCTCCTGTTTTATTTTATTAGCGATC GTGATGGGTCTGGTGTTTATCTGCGTCAAAAATGGTAATATGAGGTGTACTATATGTATC 564 ATGAACACTCAGATTCTAGTATTTGCACTTATTGCCATCATACCAACCAACGCTGACAAG ATCTGTCTCGGCCATCATGCGGTCAGTAACGGTACAAAGGTCAATACACTGACAGAACGT GGGGTAGAGGTCGTAAACGCAACCGAGACCGTGGAGAGAACCAATATTCCTCGAATATGT TCCAAAGGCAAGAGGACTGTTGATTTAGGACAGTGCGGGCTGCTGGGAACTATAACAGGG CCCCCACAATGTGATCAATTCCTCGAGTTCTCAGCCGACCTCATTATCGAGAGACGCGAG GGATCTGATGTGTGCTACCCTGGCAAATTCGTGAACGAGGAGGCCCTGCGCCAGATCTTG CGGGAAAGCGGTGGAATCGATAAGGAGGCCATGGGGTTTACTTATAGCGGCATAAGGACC AACGGCGCCACCTCTGCATGCAGGAGGAGCGGCAGTAGCTTCTACGCAGAGATGAAATGG CTGCTGTCTAATACCGACAATGCCGCGTTCCCTCAAATGACTAAAAGCTACAAGAATACG CGCAAGTCTCCAGCCCTGATCGTGTGGGGCATCCATCACAGTGTCTCAACTGCAGAACAG ACCAAACTTTACGGTTCAGGCAACAAACTCGTCACCGTCGGCTCTTCTAATTATCAACAG AGTTTCGTGCCTAGCCCAGGCGAGCGACCCCAGGTGAACGGTCTTTCCGGTCGGATCGAT TTTCACTGGCTCATGCTCAACCCGAACGATACTGTGACTTTCAGTTTCAACGGGGCCTTC ATTGCTCCGGATCGGGCATCATTTCTGAGGGGCAAGTCTATGGGCATCCAGTCCGGCGTG CAGGTGGACGCTAACTGCGAAGGTGATTGTTACCACTCGGGTGGCACAATCATTTCTAAT CTACCCTTCCAGAACATTGACTCAAGAGCTGTCGGGAAGTGTCCACGATACGTGAAGCAG AGATCCCTGCTCCTCGCCACAGGGATGAAGAATGTCCCAGAGATTCCTAAAGGGCGCGGC CTGTTCGGAGCTATAGCGGGGTTCATTGAGAATGGGTGGGAAGGCCTAATTGACGGTTGG TATGGTTTTAGGCATCAGAATGCCCAGGGCGAGGGTACCGCCGCAGATTATAAAAGTACT CAGTCTGCCATCGATCAAATCACCGGGAAGCTAAACCGGTTGATCGAAAAAACTAACCAG CAGTTTGAGCTGATTGACAACGAATTTAACGAGGTGGAGAAACAGATCGGCAACGTAATT AATTGGACGCGGGATAGCATCACAGAAGTCTGGAGCTATAATGCAGAGCTCCTGGTGGCG ATGGAGAATCAGCACACTATCGACTTGGCTGATTCGGAAATGGATAAGCTGTATGAGAGG GTGAAACGTCAGCTGCGGGAGAATGCCGAAGAAGATGGTACCGGGTGTTTCGAAATATTC CATAAATGTGACGATGATTGTATGGCCAGCATCCGAAATAACACATATGACCATTCTAAA TACAGAGAAGAGGCCATGCAGAATCGAATACAAATCGACCCTGTGAAACTGTCCTCCGGA TATAAAGATGTTATCCTTTGGTTTAGCTTCGGCGCCTCTTGCTTTATACTGTTGGCAATC GTGATGGGCTTGGTATTTATTTGTGTCAAGAATGGCAATATGCGCTGTACGATCTGCATT 565 ATGAACACCCAGATCTTGGTGTTTGCTCTTATTGCAATCATCCCTACTAACGCCGATAAA ATCTGTCTGGGTCACCATGCCGTCAGTAATGGAACCAAGGTAAACACACTGACGGAGAGG GGCGTGGAGGTGGTTAACGCAACCGAAACAGTTGAGCGGACGAATATCCCCCGGATATGT AGTAAGGGAAAGAAAACTGTCGATCTGGGACAGTGCGGCCTACTAGGAACCATCACTGGG CCTCCCCAGTGTGACCAGTTCCTGGAATTTTCTGCCGACCTGATTATCGAACGCCGTGAG GGATCCGACGTGTGCTATCCAGGTAAATTCGTGAATGAAGAAGCACTTAGGCAGATCCTT CGTGAATCTGGGGGCATCGATAAGGAAGCTATGGGGTTTACTTATTCCGGTATTAGGACC AACGGGGCAACAAGCGCCTGCAGACGAAGTGGTTCGTCATTTTACGCCGAGATGAAATGG CTGTTGTCCAACACTGACAATGCTGCTTTTCCCCAAATGACCAAAAGCTATAAAAACACT CGGAAATCACCCGCCCTCATCGTATGGGGGATCCACCATTCTGTTTCTACTGCAGAACAG ACAAAACTGTACGGGAGCGGCAATAAGCTGGTGACCGTGGGGTCCTCCAATTATCAACAG TCTTTTGTCCCGTCCCCAGGAGCGAGACCACAGGTCAATGGACAGTCAGGCCGAATCGAC TTCCACTGGCTTATGCTTAATCCAAACGACACCGTCACCTTTAGTTTCAATGGCGCCTTC ATCGCCCCAGACAGAGCCTCATTCCTGCGCGGGAAATCGATGGGCATTCAGTCGGGAGTC CAAGTGGACGCAAACTGCGAAGGTGACTGTTACCATAGTGGGGGCACAATCATCAGTAAC CTGCCCTTTCAGAACATAGATTCCCGCGCCGTAGGAAAGTGTCCCCGGTATGTGAAACAG AGATCATTGTTGCTGGCAACAGGGATGAAAAATGTACCCGAAATTCCCAAAGGGCGAGGG CTGTTTGGAGCCATTGCCGGTTTTATCGAGAACGGGTGGGAGGGCCTGATCGATGGGTGG TACGGTTTCAGACACCAGAACGCCCAGGGCGAAGGGACCGCTGCAGATTACAAGTCGACC CAATCCGCGATAGATCAGATCACTGGTAAACTCAATCGACTCATTGAAAAGACAAATCAA CAGTTCGAGCTGATTGATAACGAGTTCAACGAAGTCGAAAAGCAGATAGGGAACGTGATC AATTGGACACGCGACTCCATCACCGAAGTGTGGAGTTACAATGCAGAGCTGTTGGTAGCG ATGGAGAACCAGCATACTATTGACCTGGCCGATTCAGAAATGGACAAGCTGTACGAGCGC GTCAAGCGGCAACTGCGAGAGAATGCTGAAGAGGATGGAACCGGATGCTTCGAAATCTTC CACAAGTGCGATGACGACTGCATGGCCTCCATCAGGAACAATACATACGATCACTCAAAG TACCGGGAGGAGGCCATGCAGAACCGTATTCAGATCGACCCCGTAAAACTGAGCTCCGGC TACAAGGATGTAATCTTGTGGTTCAGCTTCGGCGCTTCATGCTTTATTTTACTGGCCATC GTCATGGGACTTGTCTTTATCTGTGTTAAGAACGGGAATATGCGGTGCACCATCTGCATC 566 ATGAATACACAGATACTGGTGTTTGCCCTCATTGCAATCATTCCAACCAATGCCGACAAG ATTTGCCTGGGCCATCACGCTGTGTCCAACGGCACCAAGGTGAACACCCTTACAGAACGC GGGGTGGAGGTGGTCAACGCAACCGAGACCGTGGAGAGAACCAATATTCCAAGGATCTGC TCGAAGGGAAAGAAGACCGTAGATCTGGGACAGTGTGGGCTGCTCGGCACAATAACCGGC CCCCCGCAGTGTGATCAGTTCTTGGAGTTCAGCGCTGATCTGATTATCGAGCGGAGGGAG GGATCCGACGTCTGTTACCCCGGGAAGTTCGTGAATGAAGAAGCTCTTAGACAGATCCTT CGCGAATCTGGCGGAATTGACAAGGAAGCTATGGGCTTCACTTATTCTGGAATAAGAACC AACGGCGCAACCTCCGCCTGTAGGCGCAGCGGATCCAGCTTTTATGCCGAGATGAAATGG TTGTTGTCCAATACTGACAATGCCGCTTTCCCCCAGATGACCAAGTCCTACAAGAATACT CGAAAAAGCCCAGCTTTGATCGTCTGGGGCATCCACCATTCTGTCTCCACCGCGGAGCAG ACCAAGCTTTATGGCTCTGGTAACAAGCTGGTGACTGTGGGAAGCAGCAATTACCAGCAA AGTTTCGTGCCTAGTCCCGGGGCCCGCCCACAGGTAAACGGCCAGTCAGGGAGAATAGAC TTCCACTGGCTGATGCTGAACCCTAATGACACGGTGACATTTAGCTTTAATGGTGCTTTC ATCGCTCCCGATCGCGCCAGTTTTCTCAGAGGGAAGTCGATGGGAATCCAATCCGGTGTC CAAGTGGACGCCAATTGTGAGGGAGACTGCTATCATAGCGGGGGAACAATCATATCTAAT CTTCCATTTCAGAACATTGATTCTCGAGCAGTTGGAAAGTGCCCCCGGTACGTGAAGCAA CGAAGCCTGCTCCTTGCAACCGGCATGAAGAATGTGCCCGAGATCCCAAAGGGACGGGGC CTATTCGGGGCCATCGCCGGGTTCATCGAGAATGGTTGGGAGGGACTAATCGATGGATGG TATGGCTTTCGGCACCAGAACGCTCAGGGCGAAGGAACCGCAGCAGACTACAAATCAACA CAGTCCGCCATAGACCAGATCACAGGTAAACTCAACCGCCTGATAGAGAAAACAAATCAG CAATTTGAACTTATCGACAATGAGTTCAACGAAGTGGAGAAACAAATAGGAAACGTAATT AACTGGACCAGGGACTCAATCACCGAAGTGTGGAGCTATAATGCCGAGCTCCTGGTGGCT ATGGAGAATCAGCATACTATCGACTTAGCTGACAGCGAGATGGACAAGCTGTATGAACGG GTCAAACGGCAGCTTAGGGAGAATGCTGAAGAGGATGGCACTGGCTGCTTCGAGATCTTC CACAAATGCGATGATGACTGTATGGCCTCTATTAGGAATAATACGTACGACCATTCTAAA TACAGGGAGGAGGCTATGCAGAACCGGATTCAGATTGATCCAGTTAAGCTGTCTAGCGGT TATAAAGATGTGATTTTGTGGTTCTCCTTTGGCGCCAGCTGTTTCATCTTGCTAGCAATA GTTATGGGCCTAGTGTTTATCTGCGTGAAGAACGGCAATATGAGATGTACAATCTGCATC 567 ATGAACACACAGATCCTGGTATTTGCTCTTATCGCTATCATCCCGACCAACGCCGATAAG ATCTGTCTTGGCCACCACGCCGTTTCGAATGGCACCAAGGTGAATACTCTTACCGAACGA GGAGTGGAAGTTGTGAACGCCACGGAAACAGTTGAACGCACCAACATCCCGAGGATCTGT TCCAAAGGCAAGAAAACGGTTGACCTGGGCCAGTGTGGACTGTTGGGGACTATCACCGGG CCCCCACAGTGTGATCAGTTCCTGGAGTTTTCTGCTGACCTGATTATTGAAAGACGGGAG GGGTCAGACGTGTGTTACCCCGGCAAGTTCGTCAATGAGGAAGCTCTTCGACAGATTTTA AGGGAATCGGGCGGAATTGACAAGGAAGCCATGGGGTTCACCTACTCTGGGATTCGTACC AACGGTGCTACCTCCGCTTGTCGAAGGTCTGGCAGTAGCTTCTACGCGGAGATGAAATGG CTCCTGTCAAACACAGACAATGCCGCGTTCCCTCAAATGACTAAGTCATACAAAAACACT CGTAAGTCCCCGGCTCTCATAGTGTGGGGCATCCACCATAGTGTGAGCACAGCGGAGCAG ACCAAATTGTACGGAAGCGGCAACAAGCTTGTGACTGTGGGTTCCTCCAACTACCAACAG AGTTTCGTGCCAAGCCCGGGCGCTCGCCCTCAGGTCAACGGCCAGTCCGGCAGAATTGAC TTCCACTGGCTCATGCTCAACCCAAACGACACAGTTACATTTAGTTTCAATGGAGCGTTC ATAGCACCTGATCGCGCTTCTTTTCTGAGAGGAAAATCCATGGGGATTCAGAGTGGTGTG CAAGTAGATGCTAACTGCGAGGGCGACTGTTACCACTCTGGCGGTACTATCATCTCCAAC CTCCCATTTCAAAACATAGATTCTCGTGCGGTGGGCAAATGTCCGAGGTACGTGAAACAG CGATCACTCCTGCTAGCCACCGGAATGAAAAACGTGCCCGAGATCCCGAAGGGCCGGGGC CTGTTCGGTGCCATCGCAGGGTTTATCGAAAACGGGTGGGAAGGCCTGATCGATGGGTGG TATGGGTTTCGGCATCAGAACGCACAGGGAGAAGGAACAGCTGCTGACTACAAAAGCACA CAGTCTGCCATCGACCAAATTACAGGTAAACTCAATAGGCTCATTGAGAAGACCAATCAG CAGTTCGAGCTCATTGACAATGAGTTTAACGAGGTCGAAAAGCAAATCGGGAATGTAATA AATTGGACCCGCGACAGTATCACAGAAGTCTGGAGTTACAACGCAGAGCTGCTCGTGGCT ATGGAGAACCAGCACACAATTGACTTGGCTGACTCCGAAATGGATAAGTTGTACGAACGA GTAAAGCGCCAGCTGCGCGAGAACGCTGAAGAGGACGGGACGGGGTGTTTCGAAATTTTC CACAAATGTGACGATGATTGCATGGCCTCTATCCGCAACAATACCTACGACCACAGCAAG TACCGCGAGGAGGCCATGCAGAACCGCATCCAAATCGACCCTGTGAAGTTGTCTTCCGGA TACAAGGATGTGATCCTGTGGTTCTCCTTTGGGGCCAGTTGCTTTATCCTTCTCGCAATT GTGATGGGACTCGTCTTTATCTGCGTGAAAAACGGTAACATGCGCTGTACAATTTGTATA 568 ATGAACACCCAGATCCTAGTCTTTGCTCTGATTGCGATCATCCCCACCAATGCGGATAAG ATCTGCCTCGGACACCACGCCGTCTCTAATGGCACGAAAGTCAACACCTTAACAGAAAGG GGGGTGGAGGTGGTTAATGCCACCGAGACAGTCGAACGAACGAATATTCCCAGAATTTGT TCTAAAGGAAAACGCACCGTGGACTTAGGGCAGTGCGGCCTCCTCGGCACTATTACCGGC CCTCCACAGTGTGACCAGTTCTTAGAGTTCAGCGCCGACCTGATCATAGAGCGAAGGGAA GGGTCTGACGTGTGCTATCCTGGCAAATTTGTGAATGAGGAGGCCTTGAGACAGATTCTT AGGGAGTCGGGCGGTATAGACAAGGAAGCTATGGGCTTTACATACAGTGGGATCCGGACA AATGGCGCGACAAGCGCATGTAGGAGAAGCGGAAGCAGCTTTTACGCTGAGATGAAGTGG CTACTCTCCAATACCGATAATGCCGCCTTCCCACAAATGACAAAATCCTATAAGAACACC AGGAAGTCCCCAGCCCTCATCGTCTGGGGAATTCACCACTCCGTCTCTACAGCAGAACAA ACTAAACTCTACGGTTCCGGAAATAAGCTCGTTACTGTCGGCAGCTCCAATTACCAGCAG TCATTCGTCCCAAGTCCCGGAGCAAGACCTCAGGTTAATGGCCTCAGCGGAAGAATCGAC TTCCACTGGTTGATGTTAAACCCGAACGACACAGTGACATTCTCCTTTAACGGAGCCTTC ATCGCACCGGATCGGGCCTCTTTTTTAAGGGGAAAGAGCATGGGCATTCAGTCCGGGGTG CAGGTCGATGCTAACTGTGAAGGCGATTGTTATCATAGCGGAGGCACCATCATCTCAAAT CTGCCTTTTCAGAACATTGACTCCAGAGCTGTAGGAAAGTGTCCTCGCTATGTGAAACAA AGGTCTCTTCTGCTGGCAACTGGAATGAAGAATGTGCCAGAGATTCCTAAGGGTCGGGGA CTATTTGGAGCCATAGCCGGCTTTATAGAAAATGGATGGGAGGGCCTGATAGACGGTTGG TACGGGTTCCGCCATCAGAATGCCCAAGGTGAGGGTACGGCCGCAGACTATAAGTCTACA CAGAGCGCCATTGATCAGATAACCGGAAAGCTGAACCGTCTGATAGAGAAAACCAACCAG CAATTTGAACTTATTGATAACGAGTTCAACGAGGTTGAGAAGCAGATCGGCAATGTTATT AACTGGACAAGAGATTCGATCACCGAAGTTTGGTCATACAACGCCGAACTGCTGGTAGCC ATGGAGAACCAGCACACAATCGACCTCGCAGATAGTGAGATGGACAAACTGTACGAGCGT GTGAAGAGACAGCTGAGAGAGAACGCGGAGGAAGACGGCACTGGCTGTTTCGAGATTTTC CATAAGTGCGATGACGATTGCATGGCCTCCATTAGGAATAATACCTATGACCATTCCAAA TACCGTGAAGAAGCCATGCAAAACCGGATCCAGATTGACCCCGTCAAGCTTTCGTCAGGG TATAAAGATGTGATCCTGTGGTTCTCTTTCGGCGCCAGTTGCTTCATCCTGCTCGCAATC GTGATGGGACTCGTGTTCATATGTGTCAAAAACGGCAACATGCGCTGTACGATCTGCATA 569 ATGAACACTCAGATCCTTGTCTTTGCCCTAATAGCAATAATTCCAACAAATGCCGATAAA ATCTGTTTGGGTCATCACGCCGTCTCAAACGGAACAAAGGTGAACACACTGACAGAACGG GGTGTCGAGGTGGTCAATGCCACCGAAACTGTCGAACGCACTAATATTCCCAGAATATGC TCGAAGGGTAAGAGGACGGTAGACTTGGGCCAGTGTGGCCTGCTTGGTACCATCACTGGC CCTCCCCAGTGTGACCAATTCCTGGAGTTTAGCGCGGACCTGATAATTGAGAGACGTGAG GGTAGCGATGTTTGCTATCCTGGAAAGTTCGTCAATGAAGAGGCCCTGAGGCAGATCCTA CGAGAATCCGGCGGGATCGATAAAGAAGCTATGGGATTTACCTACTCCGGGATCAGGACA AACGGGGCAACTTCGGCATGTCGGCGGTCTGGCAGCTCATTTTATGCTGAGATGAAATGG TTGCTCTCAAACACCGATAACGCCGCTTTCCCACAAATCACCAAGTCCTACAAGAACACA AGGAAGTCCCCCGCTTTGATTGTCTGGGGCATCCACCACAGCGTGTCAACTGCTGAGCAG ACCAAGTTATACGGCTCAGGCAACAAACTCGTTACCGTGGGATCTTCGAATTATCAACAG AGTTTTGTGCCATCCCCTGGTGCTAGGCCGCAAGTTAATGGTCTTAGTGGGCGTATAGAC TTCCACTGGCTTATGCTGAATCCGAACGATACCGTCACCTTTTCATTCAACGGTGCTTTC ATAGCCCCCGATCGCGCCTCTTTCCTCAGGGGGAAGTCTATGGGTATTCAGTCAGGTGTG CAGGTGGATGCGAATTGTGAGGGAGATTGTTACCACTCCGGGGGCACCATAATAAGCAAT CTTCCCTTTCAAAATATCGACTCTCGGGCGGTCGGAAAATGTCCGCGCTATGTGAAGCAG CGGAGTCTCCTGCTGGCAACAGGGATGAAAAATGTGCCCGAGATTCCTAAAGGAAGAGGT TTGTTTGGTGCGATCGCTGGTTTTATCGAGAATGGGTGGGAGGGCTTAATCGACGGTTGG TATGGGTTTAGACACCAGAACGCCCAGGGAGAGGGTACCGCAGCCGACTATAAGAGTACA CAGAGCGCAATCGACCAGATCACAGGCAAACTCAACCGCCTAATTGAGAAAACTAACCAG CAATTCGAGTTAATCGACAATGAGTTCAACGAGGTAGAAAAGCAAATAGGCAACGTCATT AATTGGACCCGGGACAGTATAACAGAGGTCTGGAGCTATAATGCCGAGCTGTTGGTGGCC ATGGAAAACCAGCACACGATCGACCTGGCAGACAGCGAAATGGACAAGCTGTACGAGAGA GTTAAGCGCCAGTTGCGCGAGAACGCCGAGGAAGATGGCACCGGGTGCTTCGAAATCTTT CACAAGTGCGATGACGACTGCATGGCTTCTATTCGAAATAATACTTATGATCATAGCAAG TATAGAGAAGAAGCCATGCAGAATAGGATCCAGATCGACCCAGTAAAGTTGTCTTCTGGC TACAAGGATGTGATACTGTGGTTCTCCTTTGGGGCTAGTTGCTTTATTTTGCTGGCTATT GTTATGGGTCTGGTGTTCATTTGTGTGAAGAATGGGAACATGCGCTGCACGATATGTATC 570 ATGAATACCCAGATCCTGGTGTTCGCACTGATCGCCATTATACCCACCAACGCCGACAAG ATCTGCCTTGGCCACCACGCTGTTTCTAATGGAACGAAGGTCAATACTCTGACCGAGAGG GGGGTGGAAGTCGTGAACGCTACAGAGACTGTTGAAAGGACAAATATTCCGCGCATTTGC AGCAAAGGGAAGCGAACCGTGGATTTGGGCCAATGTGGCCTCCTTGGCACTATTACAGGC CCACCTCAGTGTGATCAGTTTCTGGAATTCTCCGCTGACCTCATTATAGAACGGAGAGAA GGATCAGACGTTTGTTACCCTGGCAAATTCGTGAATGAGGAGGCCTTGAGACAGATACTC AGGGAGTCCGGCGGCATCGACAAGGAAGCAATGGGTTTCACCTACAGCGGCATTCGCACC AACGGCGCCACCTCCGCCTGCCGCCGCAGCGGGTCTAGCTTTTATGCCGAAATGAAATGG CTCTTAAGTAATACAGACAACGCTGCCTTTCCCCAGATGACAAAATCATACAAGAACACA AGAAAATCACCCGCACTTATAGTTTGGGGGATCCATCACTCCGTGTCCACCGCTGAGCAG ACTAAGTTGTACGGGAGTGGAAACAAACTGGTTACGGTGGGTAGTTCTAACTATCAGCAG TCCTTTGTGCCTTCGCCCGGAGCTCGCCCACAGGTTAACGGTCTGAGCGGTCGCATCGAC TTCCACTGGCTAATGCTGAACCCTAACGATACCGTGACATTCTCTTTTAATGGAGCTTTC ATCGCCCCCGACCGCGCTTCCTTTTTGAGGGGGAAGTCCATGGGTATCCAGAGCGGAGTG CAGGTGGACGCCAATTGCGAGGGAGATTGTTATCATTCTGGCGGCACCATTATCTCTAAT TTACCGTTTCAGAATATCGACTCAAGAGCAGTGGGCAAGTGCCCTCGATACGTGAAGCAG CGCAGCCTGCTTCTTGCTACAGGAATGAAAAACGTCCCGGAGATTCCCAAGGGGCGGGGC CTGTTCGGCGCCATCGCAGGCTTCATAGAGAACGGTTGGGAGGGACTGATTGATGGATGG TACGGGTTCCGCCATCAGAACGCCCAGGGCGAAGGAACCGCTGCGGACTACAAGTCCACC CAGTCCGCAATCGACCAGATAACGGGCAAGTTGAATAGGCTCATCGAAAAAACGAACCAA CAATTCGAGCTTATTGATAACGAGTTTAACGAAGTAGAAAAGCAGATTGGGAATGTGATA AACTGGACCAGAGATAGCATCACCGAGGTGTGGAGCTATAATGCAGAACTGCTAGTAGCT ATGGAAAATCAGCACACAATCGACTTAGCCGATAGTGAGATGGACAAATTGTATGAGCGA GTAAAAAGACAATTAAGAGAAAACGCAGAGGAGGATGGCACCGGTTGTTTCGAAATCTTT CACAAATGTGATGACGACTGTATGGCCTCAATTCGGAACAACACCTACGACCACAGCAAA TACAGAGAAGAGGCCATGCAGAATCGCATACAGATAGATCCAGTCAAACTGTCATCTGGG TACAAGGACGTTATATTATGGTTCTCTTTCGGGGCAAGCTGCTTCATCCTTCTGGCTATC GTGATGGGCTTGGTCTTCATCTGCGTCAAGAATGGAAACATGCGCTGCACCATCTGCATC 571 ATGAATACCCAGATCCTGGTTTTCGCCCTGATCGCTATCATTCCTACTAACGCAGATAAG ATCTGCCTGGGGCACCATGCAGTCAGCAACGGGACCAAGGTGAACACACTGACTGAGCGT TCCTTTGTGCCCAGCCCTGGCGCTAGACCGCAAGTGAACGGGCAGAGCGGGAGGATTGAC TTCCACTGGCTGATGCTCAATCCCAACGATACCGTAACCTTTTCATTTAACGGCGCTTTC ATCGCCCCCGATAGAGCTAGTTTCCTACGGGGAAAAAGCATGGGTATTCAAAGTGGTGTG CAGGTAGACGCAAATTGTGAAGGCGACTGTTACCATTCGGGTGGGACCATTATCTCCAAC CTGCCCTTCCAGAACATTGATTCACGCGCCGTGGGAAAGTGCCCTAGGTATGTTAAACAG AGAAGCCTGCTGTTGGCCACAGGGATGAAGAATGTGCCAGAGATTCCAAAGGGACGGGGA CTCTTTGGTGCGATCGCAGGCTTCATCGAGAACGGTTGGGAAGGGCTGATAGATGGATGG TACGGTTTCCGTCACCAGAACGCCCAAGGAGAGGGGACAGCCGCGGACTACAAATCAACG CAGTCTGCCATTGACCAAATCACTGGCAAACTGAACCGGCTTATCGAGAAAACCAACCAG CAGTTTGAACTGATAGATAATGAATTCAACGAGGTTGAGAAGCAAATTGGGAACGTCATA AATTGGACTAGAGACTCTATCACAGAGGTGTGGTCATATAATGCAGAGCTGTTGGTGGCA ATGGAAAACCAGCACACTATCGACCTAGCAGATTCTGAGATGGACAAGCTATATGAACGC GTTAAGCGGCAGCTGCGGGAAAACGCAGAAGAAGACGGTACAGGTTGTTTCGAGATATTT CACAAATGCGACGATGATTGTATGGCATCGATCAGAAATAATACGTATGACCACTCCAAA TACCGAGAAGAGGCTATGCAGAACCGAATCCAGATTGATCCTGTAAAGCTCAGTTCTGGC TACAAGGACGTCATTCTCTGGTTTAGCTTTGGAGCCTCCTGTTTCATTCTTTTGGCCATC GTTATGGGCCTCGTGTTTATTTGCGTGAAAAATGGTAATATGCGGTGTACCATATGTATC 578 ATGAATACCCAAATTCTGGTTTTTGCGCTGATCGCGATCATACCGACCAACGCGGATAAA ATTTGTCTCGGGCATCACGCCGTGAGCAATGGGACCAAGGTAAACACACTGACGGAGCGG GGGGTGGAGGTGGTGAACGCCACAGAGACGGTCGAGCGGACAAATATTCCTCGGATATGC TCCAAGGGCAAGAAGACTGTTGATTTAGGCCAGTGCGGCCTCCTCGGCACCATCACCGGA CCGCCCCAGTGCGACCAGTTCCTGGAGTTTTCCGCTGACCTGATCATCGAAAGGAGAGAG GGAAGCGATGTGTGTTACCCTGGAAAGTTTGTTAATGAGGAGGCCCTAAGACAGATTCTG CGGGAATCCGGCGGCATCGAGAAGGAGGCCATGGGATTTACTTACAGCGGGATTAGAGCG AACGGAGCTACATCTGCCTGTCGCAGGAGTGGATCTTCCTTCTACGCTGAGATGAAATGG CTGCTCTCGAATACGGACAACGCCGCGTTTCCTCAAATGACTAAATCTTACAAAAACACT CGGAAGTCCCCCGCGCTCATTGTGTGGGGAATCCACCACAGTGTGAGTACAGCCGAGCAG ACTAAACTGTATGGCAGTGGGAATAAGCTGGTCACAGTTGGGTCCTCCAACTACCAGCAG AGCTTCGTTCCCAGTCCGGGCGCACGCCCGCAGGTTAATGGCCTTAGCGGTAGAATCGAT TTCCACTGGCTGATGCTGAATCCTAACGATACTGTGACTTTCAGCTTCAATGGCGCTTTT ATTGCACCCGACAGAGCTTCTTTTCTGCGTGGCAAATCCATGGGCATTCAGTCCGGCGTG CAGGTGGACGCCAACTGCGAAGGCGATTGTTACCACTCTGGGGGCACCATCATCTCCAAC CTCCCTTTTCAAAACATAGACAGTCGCGCTGTGGGAAAATGTCCAAGGTACGTTAAACAA CGGTCTCTGCTACTGGCTACCGGCATGAAGAATGTGCCCGAAATCCCCAAGGGACGGGGC TTATTTGGCGCGATTGCCGGATTTATTGAAAATGGCTGGGAGGGCCTCATTGACGGATGG TACGGTTTTCGACACCAGAACGCTCAGGGTGAAGGGACCGCTGCAGACTACAAATCCACG CAGTCCGCTATCGATCAGATTACAGGAAAGCTGAACAGACTAATCGAGAAGACTAATCAG CAGTTCGAGCTAATCGATAATGAGTTCAACGAGGTCGAAAAGCAGATTGGGAACGTCATC AACTGGACTCGCGATAGCATCACGGAGGTATGGTCTTATAATGCAGAGTTGCTGGTGGCC ATGGAAAATCAGCATACAATCGACTTGGCTGACTCTGAGATGGATAAATTGTATGAGAGG GTAAAAAGGCAGTTGAGAGAGAACGCGGAGGAAGATGGCACTGGTTGCTTCGAGATCTTT CACAAGTGTGACGACGATTGCATGGCCAGTATTAGAAATAATACATATGACCACAGCAAG TACAGGGAGGAGGCCATGCAGAATCGTATCCAAATCGATCCCGTGAAATTGTCAAGCGGA TATAAAGACGTTATACTATGGTTCTCCTTTGGGGCTAGTTGTTTCATTCTCCTGGCGATC GTCATGGGCCTGGTTTTCATCTGCGTTAAGAATGGGAATATGAGATGTACTATCTGCATC 579 ATGAATACCCAGATTCTGGTGTTCGCTCTCATTGCAATAATCCCGACTAACGCTGATAAA ATCTGTCTTGGCCACCACGCTGTGAGTAATGGAACGAAAGTCAATACGCTCACTGAGCGG GGAGTCGAAGTTGTTAACGCTACCGAGACCGTGGAGCGGACAAACATACCGCGGATTTGC TCAAAGGGCAAAAAGACAGTGGATCTGGGTCAGTGCGGCCTTCTCGGCACAATCACCGGG CCCCCACAGTGTGACCAATTTCTCGAGTTTTCAGCTGATTTGATAATTGAGCGCCGGGAG GGCAGTGATGTATGCTATCCAGGGAAGTTCGTGAATGAAGAGGCCCTCCGCCAAATTCTC CGGGAATCTGGCGGGATTGACAAGGAAGCCATGGGGTTCACTTACTCTGGAATTCGGACT AATGGTGCTACCAGTGCTTGCCGTAGAAGTGGTAGCAGTTTCTATGCCGAAATGAAATGG TTGTTAAGCAATACCGATAACGCAGCATTTCCCCAGATGACAAAGTCGTACAAAAACACC AGGAAAAGTCCTGCTCTGATCGTGTGGGGTATCCATCACTCTGTGAGTACAGCAGAACAG ACTAAACTGTATGGATCAGGCAATAAGTTGGTGACAGTAGGCTCTTCGAATTACCAACAG TCATTTGTCCCCAGCCCGGGAGCCCGGCCACAGGTCAACGGCCAAAGCGGACGCATCGAT TTCCACTGGCTTATGCTGAATCCTAATGACACCGTCACATTTTCCTTCAATGGGGCCTTT ATTGCCCCAGATCGTGCATCCTTTCTGAGAGGGAAATCCATGGGTATACAGAGCGGGGTG GGAGTCGAGGTCGTCAATGCGACTGAGACAGTAGAGCGGACGAACATACCCAGAATCTGC AGCAAAGGGAAACGGACGGTAGACCTCGGCCAGTGCGGTCTCCTGGGTACCATCACAGGT CCACCCCAATGCGATCAGTTTCTGGAGTTCTCCGCCGACCTCATCATCGAACGGCGCGAG GGGTCCGATGTCTGCTACCCTGGTAAATTCGTCAATGAAGAGGCTCTCCGTCAGATTCTT CGGGAATCAGGGGGGATTGACAAGGAAGCTATGGGATTTACATACTCCGGTATACGAACC AACGGAGCTACCAGTGCTTGCCGACGGTCAGGGTCATCATTCTACGCCGAGATGAAATGG CTTCTCTCGAACACTGATAATGCTGCGTTTCCACAAATTACCAAAAGCTACAAAAACACC CGGAAGTCCCCTGCACTGATCGTGTGGGGAATTCACCACAGCGTCTCTACGGCTGAACAG ACCAAACTGTACGGATCAGGCAACAAGTTGGTGACTGTCGGGTCATCCAATTATCAGCAG AGTTTCGTTCCCAGCCCTGGCGCAAGACCTCAGGTGAACGGCTTGTCCGGGAGGATTGAT TTTCACTGGCTCATGCTGAATCCTAATGACACTGTTACCTTTTCTTTTAATGGGGCTTTT ATTGCACCGGACCGAGCAAGTTTTCTACGCGGAAAGTCCATGGGGATACAGAGTGGGGTG CAGGTGGATGCTAATTGCGAGGGCGATTGTTATCACAGCGGCGGCACCATAATATCAAAC CTGCCCTTCCAGAACATCGACTCCAGGGCCGTGGGCAAGTGTCCAAGATACGTCAAACAA AGATCTCTGCTGCTGGCCACTGGGATGAAAAACGTCCCAGAAATCCCAAAAGGGAGGGGG CTCTTCGGAGCCATAGCCGGGTTTATCGAAAATGGATGGGAAGGTCTGATAGACGGGTGG TACGGTTTCAGACATCAGAACGCACAGGGCGAGGGAACAGCCGCCGACTACAAGAGCACC CAGAGTGCAATCGATCAGATCACTGGTAAGCTTAATAGGCTGATCGAAAAGACTAATCAA CAATTTGAGCTGATAGACAATGAATTCAACGAAGTTGAAAAGCAGATAGGTAATGTAATC AATTGGACCCGAGATTCAATAACTGAAGTCTGGAGCTACAATGCCGAACTGTTGGTGGCT ATGGAGAACCAACATACGATTGACCTGGCCGACTCCGAGATGGACAAGCTGTATGAGCGG GTAAAGAGACAGCTGAGGGAGAATGCCGAGGAAGATGGCACCGGATGTTTCGAGATTTTT CACAAGTGTGATGACGACTGCATGGCGTCTATCCGGAATAACACCTACGACCACTCAAAA TATCGGGAAGAAGCGATGCAGAATCGAATTCAGATCGACCCAGTCAAACTGTCGAGTGGC TATAAAGATGTGATACTGTGGTTTAGCTTCGGGGCATCTTGTTTCATTCTGCTGGCTATT GTGATGGGCCTCGTGTTCATTTGCGTTAAGAATGGGAATATGCGATGCACCATTTGTATC 572 ATGAATACTCAAATACTTGTCTTTGCACTAATCGCTATCATACCCACTAATGCCGATAAA ATCTGCTTAGGACACCATGCTGTGTCCAACGGAACTAAAGTGAACACTCTGACGGAGCGA GGCGTCGAAGTTGTCAACGCAACCGAGACTGTGGAGCGCACGAATATCCCCCGAATCTGC TCGAAAGGAAAGAAGACTGTTGACCTTGGTCAATGCGGATTACTGGGAACCATCACAGGA CCCCCCCAATGCGACCAGTTTCTGGAATTTAGTGCTGATCTTATAATCGAGCGCCGGGAA GGTAGCGACGTTTGTTATCCGGGAAAGTTTGTAAACGAGGAGGCTCTGAGACAGATCCTG CGCGAGTCAGGGGGGATCGACAAGGAGGCCATGGGCTTTACCTACTCTGGAATCAGAACA AATGGCGCTACTTCCGCTTGTCGGCGCTCTGGAAGCAGCTTCTATGCTGAAATGAAATGG CTGCTGTCCAACACCGACAATGCAGCCTTTCCTCAGATGACTAAATCTTACAAAAATACC CGGAAATCCCCAGCTCTGATAGTGTGGGGTATCCATCACTCAGTCAGTACTGCTGAACAA ACCAAGTTATATGGCTCCGGCAATAAGCTAGTAACCGTGGGAAGCTCCAACTACCAACAG TCTTTCGTGCCCTCACCCGGCGCAAGACCCCAGGTGAACGGCCAGTCAGGTCGCATTGAT TTCCACTGGTTGATGCTTAACCCAAATGACACCGTTACCTTTTCCTTCAATGGCGCCTTT ATAGCGCCCGACAGAGCTTCATTCCTTAGAGGCAAGTCTATGGGTATCCAATCCGGAGTC CAGGTAGACGCAAACTGTGAGGGAGACTGCTATCATTCCGGTGGAACCATCATATCGAAT TTGCCTTTCCAGAACATCGATAGCCGGGCGGTCGGCAAGTGCCCTAGATACGTTAAACAA AGGAGCCTGCTCTTAGCAACAGGTATGAAGAACGTCCCAGAGATTCCAAAGGGCCGAGGA CTGTTCGGTGCAATAGCTGGCTTTATCGAGAATGGGTGGGAGGGGCTCATCGATGGTTGG TATGGGTTCAGACACCAGAATGCCCAGGGCGAAGGAACCGCTGCTGACTACAAAAGCACA CAGAGCGCTATAGATCAGATAACAGGCAAGCTTAACCGGCTGATCGAGAAAACGAATCAG CAGTTCGAACTCATTGATAATGAGTTCAACGAAGTGGAGAAGCAGATTGGTAATGTCATC AACTGGACTAGAGATAGTATAACAGAAGTGTGGTCTTATAACGCCGAACTCCTGGTCGCA ATGGAAAATCAACATACCATTGACCTGGCTGATTCGGAGATGGACAAACTTTATGAGCGG GTGAAGAGGCAGCTCCGAGAGAATGCAGAAGAGGACGGCACAGGGTGCTTTGAGATCTTC CATAAGTGCGACGATGATTGCATGGCTTCCATCAGGAATAATACTTATGACCACTCCAAG TACCGGGAGGAAGCCATGCAAAATCGGATCCAAATAGATCCAGTGAAGCTTTCGTCAGGA TATAAGGACGTGATCTTGTGGTTTAGCTTCGGGGCCTCTTGTTTCATCCTCCTGGCGATT GTCATGGGACTTGTATTCATTTGTGTGAAGAACGGAAACATGCGCTGCACCATTTGCATA 573 ATGAACACACAGATCCTTGTGTTCGCCCTTATCGCAATAATTCCCACAAACGCCGACAAA ATATGCCTGGGTCACCACGCCGTAAGCAATGGCACCAAAGTTAACACCCTCACCGAGCGT GGGGTGGAGGTGGTGAACGCCACCGAGACCGTTGAAAGGACAAACATTCCACGAATTTGT AGTAAGGGCAAACGGACTGTAGATCTGGGTCAGTGTGGGCTGCTGGGCACTATCACCGGC CCACCACAGTGCGACCAATTCCTAGAATTCTCAGCTGATTTAATCATCGAAAGGCGCGAG GGGTCTGACGTCTGTTACCCGGGAAAATTTGTGAACGAAGAGGCCCTGCGACAGATTCTG CGTGAGTCCGGGGGAATCGACAAAGAGGCGATGGGATTTACCTATTCAGGCATACGGACC AATGGAGCTACTTCTGCATGCCGGAGGAGCGGCTCGTCTTTCTACGCTGAAATGAAGTGG TTGCTGAGTAATACCGACAACGCAGCCTTCCCCCAGATGACAAAGAGCTACAAGAACACA CGCAAGTCACCCGCACTCATAGTCTGGGGGATTCATCACTCAGTCAGTACCGCGGAGCAG ACCAAGCTCTACGGTAGCGGCAACAAGCTGGTCACAGTTGGTTCTAGTAATTACCAGCAG TCCTTTGTTCCCTCCCCCGGCGCCCGTCCCCAAGTCAACGGGCTCTCGGGCAGAATCGAC TTCCACTGGCTCATGTTGAACCCCAACGATACTGTGACATTCTCTTTTAATGGTGCTTTT ATCGCGCCGGACAGGGCCTCTTTCTTACGCGGCAAGAGCATGGGTATACAGTCTGGAGTC CAGGTTGATGCTAATTGCGAAGGCGACTGTTATCATTCAGGAGGCACCATCATATCAAAC CTGCCCTTCCAAAATATAGATAGTCGGGCTGTGGGTAAATGCCCTAGGTACGTCAAGCAG AGAAGTCTTCTGCTCGCCACTGGCATGAAAAACGTACCAGAGATTCCTAAAGGAAGAGGC CTATTTGGAGCAATTGCCGGCTTTATCGAGAATGGGTGGGAAGGCCTTATAAACGGGTGG TATGGCTTCAGGCACCAGAACGCCCAGGGGGAGGGTACCGCCGCCGATTACAAGAGCACT CAGAGTGCCATAGACCAGATTACTGGAAAATTAAATAGACTGATTGAGAAAACAAACCAG CAGTTTGAACTGATTGACAATGAATTCAATGAGGTGGAGAAGCAGATTGGGAACGTGATC AATTGGACCCGGGACTCTATTACTGAGGTATGGAGCTATAACGCTGAGCTTTTGGTGGCC ATGGAGAACCAACATACGATTGATCTGGCAGATAGCGAAATGGATAAGCTTTATGAGCGT GTTAAGAGGCAGCTCCGCGAAAATGCCGAAGAGGATGGTACGGGATGCTTCGAGATTTTC CATAAATGCGACGACGATTGCATGGCTAGCATTAGGAACAACACCTATGACCACAGTAAA TATAGAGAGGAGGCCATGCAAAATCGCATTCAGATAGACCCTGTCAAGTTGAGCTCGGGG TATAAGGACGTCATACTTTGGTTTAGTTTTGGGGCGAGCTGTTTTATTTTGCTGGCCATA GTTATGGGTCTGGTCTTTATTTGTGTAAAGAACGGGAATATGCGTTGCACCATTTGCATA 574 ATGAACACCCAAATATTAGTGTTCGCCCTCATAGCAATCATTCCCACAAATGCTGATAAG ATTTGCCTTGGTCATCATGCTGTGAGTAACGGGACCAAGGTGAACACTCTTACGGAGCGC GGGGTTGAAGTTGTTAACGCTACCGAGACCGTTGAAAGAACCAACATCCCACGAATCTGC AGCAAGGGGAAGCGGACCGTGGACTTGGGACAGTGTGGGTTGTTGGGGACTATCACCGGG CCCCCTCAGTGCGACCAGTTCCTCGAATTCAGCGCCGATCTGATCATAGAGCGACGGGAG GGGAGTGACGTTTGCTACCCCGGTAAATTCGTGAAGGAAGAAGCCCTGAGACAGATTCTA CGGGAGTCTGGCGGCATAGATAAAGAGGCTATGGGTTTCACATATAGCGGCATCCGCACA AACGGAGCCACTTCTGCCTGCAGGAGATCTGGCTCCTCTTTTTACGCTGAAATGAAATGG TTACTGTCCAACACCGACAATGCCGCCTTTCCCCAAATGACCAAGTCATACAAGAATACC CGGAAATCCCCAGCTTTGATCGTTTGGGGTATCCATCACTCAGTTTCTACCGCGGAGCAG ACTAAACTCTATGGCTCTGGAAATAAGCTGGTGACAGTGGGCTCTTCCAATTATCAGCAG TCGTTTGTTCCGTCCCCTGGCGCTAGACCACAGGTGAACGGCCTGTCCGGGCGAATCGAT TTCCACTGGCTGATGCTGAACCCGAACGACACCGTCACATTTAGCTTCAATGGAGCCTTC ATTGCTCCCGATCGAGCTTCTTTCCTGCGGGGCAAATCAATGGGCATACAATCGGGTGTG CAGGTGGACGCCAATTGTGAGGGAGACTGTTACCATTCAGGCGGCACCATTATTAGCAAT CTACCATTCCAGAATATAGACTCCCGGGCTGTTGGCAAGTGCCCCCGGTATGTTAAACAG CGGTCCCTGCTCCTGGCTACCGGTATGAAGAATGTTCCGGAAATCCCGAAGGGGCGCGGA CTCTTCGGCGCTATCGCGGGTTTTATCGAGAACGGGTGGGAGGGCCTTATCGATGGGTGG TACGGCTTCCGGCACCAGAATGCCCAGGGAGAAGGCACCGCCGCCGACTATAAGTCAACA CAGTCCGCAATTGACCAAATCACCGGTAAGCTGAATCGCTTAATTGAGAAAACCAACCAA CAATTCGAACTGATTGATAACGAATTCAACGAGGTCGAAAAGCAGATCGGGAATGTGATC AACTGGACCCGCGATAGCATTACCGAGGTCTGGTCTTACAACGCAGAACTTCTCGTTGCG ATGGAGAATCAACACACTATTGATCTGGCTGACTCCGAGATGGACAAGCTGTACGAGCGC GTGAAGCGCCAGCTGCGGGAAAATGCAGAAGAGGATGGCACTGGCTGCTTCGAGATCTTC CACAAGTGCGATGATGATTGCATGGCATCGATCAGGAACAATACATACGACCACTCGAAG TACAGAGAGGAGGCTATGCAGAACCGAATACAGATAGATCCAGTTAAACTATCATCCGGG TACAAGGACGTTATCCTGTGGTTCTCATTTGGAGCATCCTGCTTCATTCTTCTCGCAATC GTCATGGGACTGGTTTTCATCTGTGTGAAGAACGGCAACATGCGGTGCACCATCTGCATC 575 ATGAATACCCAGATATTAGTATTTGCCCTTATAGCCATCATCCCTACTAACGCGGACAAA ATCTGCCTGGGACACCATGCCGTTTCTAACGGTACAAAAGTCAACACCTTAACGGAACGG GGGGTGGAAGTGGTTAATGCTACAGAGACCGTTGAACGCACCAACATCCCCCGCATTTGC TCCAAAGGGAAGAAAACTGTGGACCTAGGTCAGTGTGGCCTGTTGGGTACTATCACCGGC CCACCTCAATGCGACCAGTTTCTGGAGTTCAGCGCCGATCTGATCATCGAAAGAAGAGAG GGTAGCGACGTTTGTTATCCTGGAAAGTTTGTTAATGAAGAGGCTCTGAGACAGATTTTG CGAGAATCCGGGGGAATCGACAAGGAAGCCATGGGCTTTACATACTCTGGTATTAGGACC AACGGTGCCACTTCTGCCTGCAGACGGAGCGGTAGTTCTTTTTACGCCGAAATGAAATGG CTATTGTCTAATACGGATAACGCTGCATTTCCTCAGATGACGAAATCATACAAAAATACA AGGAAAAGCCCCGCTCTGATTGTGTGGGGTATCCACCACTCCGTATCCACAGCAGAACAA ACAAAGCTGTATGGATCTGGTAACAAGCTCGTGACGGTGGGCTCTAGCAACTATCAGCAG AGTTTTGTGCCATCACCTGGCGCAAGACCCCAGGTCAACGGCCAGTCCGGCCGAATCGAC TTCCACTGGCTTATGCTAAACCCCAACGACACGGTGACTTTCAGTTTTAACGGCGCCTTT ATCGCTCCTGATCGCGCTTCTTTCCTTAGGGGTAAATCTATGGGGATACAATCAGGAGTG CAGGTAGACGCTAACTGCGAAGGAGACTGCTATCACTCTGGAGGAACGATAATCTCCAAT TTACCCTTCCAGAACATAGACAGTCGGGCCGTCGGGAAATGCCCCAGGTACGTGAAGCAG CGGTCTCTTCTGCTCGCGACTGGCATGAAAAACGTTCCCGAGATACCCAAGGGAAGGGGC CTGTTCGGCGCAATTGCTGGGTTCATTGAAAACGGCTGGGAGGGCCTTATTGATGGTTGG TACGGATTCAGACACCAGAATGCACAGGGCGAGGGCACAGCCGCCGATTATAAGTCAACG CAGTCAGCGATAGACCAGATAACCGGGAAATTGAACCGTCTGATTGAGAAAACAAACCAG CAATTCGAATTGATTGATAACGAGTTTAATGAGGTGGAAAAGCAGATTGGAAACGTCATT AACTGGACACGAGATTCAATTACAGAGGTGTGGAGCTATAACGCGGAGTTGCTGGTCGCT ATGGAAAACCAACATACTATAGATCTTGCCGATTCCGAGATGGACAAACTCTATGAGAGA GTCAAACGACAATTAAGGGAAAACGCCGAGGAAGATGGCACCGGATGCTTCGAAATCTTC CATAAGTGCGATGACGACTGTATGGCATCTATTCGCAACAACACGTACGATCACTCGAAA TATCGGGAAGAGGCCATGCAGAATAGGATCCAGATTGACCCTGTCAAATTGAGCAGCGGC TACAAGGATGTTATTCTGTGGTTCAGTTTCGGCGCCTCCTGTTTCATCTTACTCGCTATT GTCATGGGCTTAGTGTTCATCTGTGTCAAGAATGGCAATATGCGGTGCACTATATGCATT 576 ATGAACACTCAGATTCTGGTGTTCGCCCTAATTGCCATTATTCCCACCAATGCCGACAAA ATTTGCCTGGGCCATCATGCCGTCTCGAACGGTACCAAAGTCAATACCCTGACAGAGCGC GGCGTGGAGGTGGTGAATGCAACTGAGACCGTCGAGAGGACTAATATCCCCAGAATTTGC TCAAAGGGAAAGAAAACAGTGGATCTGGGTCAGTGCGGTCTCTTAGGGACTATCACTGGT CCTCCTCAGTGCGACCAGTTTCTGGAATTTAGTGCTGATCTGATTATCGAGCGGCGCGAA GGGTCCGACGTTTGCTACCCCGGAAAGTTTGTTAACGAGGAAGCCTTGCGGCAAATCCTG CGGAAGTCCGGCGGCATCGACAAGGAGGCCATGGGCTTTACATACTCTGGCATCCGCACC AACGGAGCTACCAGCACCTGTAGGAGGTCTGGTAGTTCATTCTATGCTGAGATGAAGTGG CTGCTCAGTAATACCGACAATGCTGCTTTTCCTCAGATGACAAAATCATACAAGAACACG AGAAAAAGCCCAGCTATTATTGTATGGGGGATTCATCATTCTGTCAGTACCGCTGAGCAG ACTAAGCTTTACGGTAGCGGAAATAAGCTTGTCACAGTGGGGTCCAGCAATTACCAGCAG TCGTTTGTTCCCTCCCCAGGAGCACGCCCCCAAGTCAACGGTCTATCGGGGAGGATCGAC TTCCATTGGCTGATGCTCAATCCTAACGACACCGTGACATTCTCTTTCAATGGCGCCTTT ATCGCACCGGACCGTGCCTGTTTTTTACGCGGTAAGTCAATGGGGATACAATCTGGAGTC CAGGTGGACGCCGACTGTGAAGGGGACTGCTATCATTCGGGTGGTACTATTATCAGCAAT CTGCCCTTCCAAAACATAGACTCAAGAGCTGTTGGAAAGTGCCCGAGATACGTGAAGCAA AGGTCACTCTTGCTTGCAACCGGGATGAAGAACGTGCCTGAGATCCCGAAGGGCCGAGGG CTGTTTGGTGCTATAGCTGGCTTCATCGAGAATGGATGGGAGGGTTTAATTGACGGCTGG TATGGATTTCGGCACCAGAATGCACAGGGAGAAGGGACCGCCGCCGATTACAAAAGTACG CAGAGTGCTATCGATCAGATTACCGGTAAATTGAATAGGCTGATTGAAAAAACTAACCAG CAGTTCGAGCTGATTGATAACGAGTTCAACGAGGTCGAGAGACAGATTGGGAACGTCATT AATTGGACGAGAGACTCAATCACGGAGGTCTGGAGCTACAATGCTGAGCTGTTAGTAGCA ATGGAAAATCAGCACACTATTGACCTCGCCGACTCCGAGATGGACAAACTGTACGAACGG GTGAAGCGGCAACTTCGCGAAAACGCTGAGGAAGACGGCACGGGATGTTTCGAAATCTTC CATAAATGCGACGATGACTGCATGGCCTCTATCCGTAATAACACATATGACCATAGTAAG TATAGGGAGGAAGCCATGCAGAATCGAATCCAGATCGACCCCGTGAAGCTGAGCTCCGGC TACAAAGACGTCATCCTCTGGTTTAGCTTTGGGGCGTCTTGTTTCATTCTCCTCGCGATC GTGATGGGTCTTGTCTTCATTTGCGTGAAAAACGGGAATATGAGGTGTACCATTTGTATC 577 ATGAATACCCAAATACTTGTGTTTGCCTTGATTGCCATAATTCCTACCAATGCCGACAAA ATCTGCCTGGGCCATCATGCCGTTAGTAATGGGACTAAGGTGAACACCCTGACAGAACGT GGCGTGGAGGTGGTCAACGCAACAGAAACCGTCGAGAGGACCAACATTCCTCGGATATGT TCGAAGGGAAAGAAGACGGTGGACCTGGGGCAATGCGGGCTGCTCGGCACCATTACGGGT CCACCTCAGTGTGATCAGTTTCTCGAGTTTTCTGCAGACCTCATCATTGAACGTAGAGAG GGCTCAGACGTGTGTTACCCAGGCAAATTTGTTAACGAGGAAGCCCTGCGCCAGATCCTG CGAGAATCTGGCGGCATTGACAAAGAGGCTATGGGATTCACGTACTCTGGTATCCGTACC AACGGCGCCACGTCCGCCTGTAGAAGGTCAGGCTCATCTTTTTACGCCGAGATGAAATGG CTCCTGTCTAATACGGACAATGCCGCATTTCCTCAGATGACCAAAAGTTACAAAAACACC CGGAAGAGTCCAGCTCTGATTGTGTGGGGCATCCATCACAGCGTGTCAACTGCGGAACAG ACCAAGCTGTATGGGTCCGGCAATAAACTGGTGACTGTGGGTTCCAGCAATTACCAGCAA CAGGTGGACGCAAACTGTGAGGGAGATTGTTACCATTCTGGCGGTACGATCATCAGCAAC TTGCCATTCCAGAATATAGACTCCCGGGCAGTCGGTAAGTGTCCCCGGTACGTCAAACAA AGAAGCTTGCTGCTGGCCACCGGGATGAAAAATGTTCCCGAGATCCCCAAGGGGCGTGGC CTCTTTGGCGCAATCGCAGGGTTTATCGAGAATGGGTGGGAAGGGCTGATCGACGGCTGG TATGGATTCAGGCACCAAAACGCACAGGGAGAAGGGACAGCCGCCGACTACAAAAGCACA CAGAGTGCGATCGATCAAATCACAGGTAAATTGAACCGACTGATTGAGAAGACAAACCAA CAGTTTGAGCTCATAGATAATGAGTTCAACGAGGTGGAGAAGCAGATAGGAAATGTGATC AACTGGACAAGGGATTCCATCACTGAAGTCTGGTCCTATAATGCCGAGCTGTTGGTTGCC ATGGAAAACCAGCATACCATTGACCTCGCCGATTCCGAAATGGATAAGCTGTACGAAAGG GTGAAGCGGCAGTTGCGGGAGAACGCAGAAGAAGATGGAACAGGATGCTTTGAGATATTT CACAAATGCGATGATGATTGCATGGCCTCGATACGCAACAATACCTATGACCATAGCAAG TACCGAGAGGAGGCGATGCAAAACAGGATCCAGATTGACCCAGTGAAGCTCAGCAGTGGG TACAAGGATGTCATTTTGTGGTTTAGCTTTGGAGCCTCATGCTTCATACTCCTCGCCATC GTCATGGGGTTGGTATTTATCTGCGTCAAGAACGGCAATATGAGGTGTACTATCTGCATC 580 ATGAATACTCAGATTCTGGTGTTTGCGCTTATCGCTATTATACCCACTAATGCCGACAAA ATCTGTCTGGGCCATCACGCCGTTAGCAACGGCACCAAAGTGAACACACTCACAGAACGT GGTGTGGAAGTCGTCAATGCCACCGAGACAGTTGAGCGCACCAATATTCCTAGAATCTGT TCCAAAGGCAAAAAAACTGTCGATCTAGGCCAATGCGGACTGCTCGGAACTATTACTGGA CCACCGCAGTGCGATCAGTTCCTCGAGTTCAGCGCAGACCTGATCATAGAGAGGAGAGAA GGTAGCGACGTTTGTTACCCTGGAAAATTTGTCAACGAGGAGGCGCTTCGACAGATTCTC AGAGAGAGTGGAGGTATAGATAAGGAGGCCATGGGTTTCACGTATTCAGGTATCAGAACG AATGGGGCAACCAGTGCCTGTCGCCGGTCAGGCAGCAGCTTCTATGCAGAGATGAAGTGG CTCCTGTCAAACACAGACAATGCTGCATTCCCACAGATGACCAAGAGCTACAAGAACACG CGAAAGTCACCTGCATTAATAGTCTGGGGTATCCACCACTCTGTCTCCACTGCCGAACAG ACCAAACTTTACGGATCTGGAAATAAGCTGGTCACTGTGGGGTCTTCTAATTATCAGCAG AGTTTTGTACCCTCGCCCGGGGCCCGGCCCCAGGTAAACGGACAGTCCGGACGGATTGAC TTTCACTGGCTCATGCTTAACCCAAACGACACAGTGACCTTCAGTTTTAACGGCGCTTTC ATCGCTCCCGACAGGGCCTCATTCCTGAGGGGAAAGTCGATGGGAATCCAGAGCGGGGTT CAGGTTGATGCAAATTGCGAAGGGGATTGTTACCATTCCGGCGGAACCATTATCTCCAAC CTGCCATTTCAGAATATAGATAGCCGCGCCGTGGGAAAGTGCCCTAGGTACGTCAAACAG CGGTCTCTGCTCCTGGCTACAGGCATGAAAAATGTTCCGGAAATCCCAAAGGGGCGGGGA CTCTTCGGAGCCATCGCAGGCTTCATCGAAAACGGCTGGGAGGGGTTAATCGATGGATGG TATGGCTTCCGCCATCAGAACGCACAGGGGGAGGGCACCGCGGCCGATTATAAGAGTACC CAGAGCGCAATAGATCAGATAACTGGTAAGTTGAATCGGTTAATTGAAAAAACTAACCAG CAGTTCGAACTAATCGATAATGAGTTCAATGAAGTCGAGAAACAGATAGGCAACGTTATC AATTGGACCAGGGACAGCATAACAGAAGTGTGGTCCTATAACGCCGAACTCCTCGTTGCC ATGGAGAACCAGCATACCATTGACCTGGCTGATTCAGAGATGGATAAACTATACGAACGG GTCAAGCGTCAATTGAGAGAGAATGCGGAAGAGGACGGGACTGGGTGCTTCGAAATCTTC CATAAGTGTGATGACGATTGTATGGCGTCCATTCGCAATAACACCTACGATCATTCAAAA TACCGTGAAGAGGCGATGCAGAATAGGATTCAGATCGACCCAGTGAAGCTCAGTAGTGGA TATAAAGACGTAATTCTCTGGTTCTCTTTCGGAGCTAGCTGCTTCATTCTTCTGGCCATC GTGATGGGACTCGTTTTCATATGTGTTAAAAATGGCAACATGCGTTGCACAATCTGTATC 581 ATGAACACTCAGATTTTAGTTTTCGCTCTAATTGCCATTATTCCTACAAATGCTGATAAA ATATGCCTGGGACACCATGCTGTCTCCAACGGTACCAAAGTCAATACTCTTACGGAGAGG GGGGTGGAGGTAGTGAACGCCACCGAGACAGTCGAACGTACAAATATACCTCGGATTTGC TCCAAGGGAAAGAAGACAGTGGATCTGGGGCAATGTGGTCTGCTGGGAACTATCACAGGC CCACCGCAGTGCGACCAGTTTCTTGAGTTTTCAGCCGACCTGATCATCGAGCGACGCGAG GGCAGCGACGTGTGTTACCCCGGGAAGTTCGTAAACGAGGAAGCTCTCCGCCAGATCCTG CGCGAGAGTGGAGGTATTGATAAGGAGGCCATGGGCTTTACATATTCTGGCATCCGGACC AATGGGGCCACAAGCGCCTGTAGGAGATCTGGATCCAGTTTTTACGCCGAAATGAAATGG CTGCTGAGCAACACAGACAATGCCGCCTTTCCTCAGATGACAAAGAGCTACAAAAACACA AGGAAGTCACCCGCCCTTATTGTCTGGGGTATCCATCACTCTGTCAGTACAGCTGAGCAG ACCAAGCTGTATGGTTCTGGCAATAAATTGGTTACCGTCGGGAGCAGTAACTATCAACAA TCATTTGTTCCAAGTCCAGGAGCCCGGCCCCAGGTCAATGGTCAAAGTGGAAGGATTGAC TTTCACTGGTTAATGCTTAATCCCAACGATACCGTGACCTTCTCATTTAATGGGGCCTTT ATTGCTCCGGACCGTGCCAGCTTTCTCCGCGGTAAGTCCATGGGCATCCAGTCCGGCGTA CAAGTGGATGCCAATTGCGAAGGCGACTGTTACCACTCTGGCGGCACCATCATCTCAAAC CTTCCGTTCCAGAACATAGATAGTCGGGCCGTGGGCAAGTGCCCTAGGTATGTGAAGCAG CGCTCATTACTGTTGGCTACTGGCATGAAAAATGTGCCAGAGATCCCTAAAGGTCGTGGT CTTTTTGGAGCTATCGCTGGGTTCATTGAAAATGGATGGGAGGGGCTGATCGACGGTTGG TACGGATTCCGGCATCAGAATGCACAGGGCGAAGGCACAGCCGCTGATTACAAGAGCACC CAGTCAGCTATTGACCAGATCACAGGGAAGCTGAACCGGCTAATCGAGAAAACAAACCAA CAATTTGAACTTATCGATAACGAATTTAATGAGGTGGAGAAACAGATAGGCAACGTGATC AACTGGACACGGGATAGTATCACTGAGGTGTGGAGTTACAATGCCGAACTCTTGGTGGCT ATGGAGAATCAGCATACTATCGATCTAGCGGACTCTGAGATGGACAAACTCTATGAACGA GTGAAGAGGCAGCTTCGCGAGAACGCTGAGGAAGATGGGACAGGGTGTTTTGAAATTTTT CATAAGTGTGATGATGATTGCATGGCATCTATCCGGAATAACACATACGACCATTCCAAG TACCGTGAAGAGGCTATGCAAAACCGAATTCAGATAGACCCAGTGAAGCTCTCTTCCGGA TACAAGGATGTAATTCTGTGGTTTTCATTCGGTGCATCCTGCTTCATCCTGCTTGCAATC GTGATGGGTTTAGTGTTCATCTGTGTGAAGAATGGGAATATGAGGTGTACAATTTGCATC 582 ATGAACACGCAGATCCTGGTGTTCGCACTGATTGCAATTATTCCCACCAATGCCGATAAG ATCTGTTTAGGACATCACGCCGTGTCCAACGGTACGAAGGTGAACACATTGACCGAGCGG GGAGTCGAAGTGGTAAATGCAACCGAGACTGTTGAACGCACAAATATCCCAAGAATTTGT TCAAAGGGTAAAAAAACCGTGGACCTCGGACAGTGCGGGCTGCTTGGAACGATTACAGGA CCTCCACAATGCGACCAGTTCCTGGAATTTTCCGCTGACCTCATCATAGAACGACGGGAA GGGTCCGACGTGTGTTATCCGGGAAAGTTCGTTAACGAGGAGGCTCTGAGGCAGATCTTG AGGGAGAGTGGTGGCATCGACAAGGAGGCGATGGGCTTCACATACAGTGGCATCAGAACT AACGGAGCCACCAGCGCATGTCGACGGTCTGGTAGCAGTTTTTATGCAGAGATGAAGTGG TTGCTGAGCAATACAGATAATGCCGCATTCCCCCAAATGACAAAGTCCTATAAGAACACG CGGAAAAGTCCTGCCCTAATTGTGTGGGGAATCCACCACTCTGTTAGTACCGCTGAGCAG ACCAAGTTATACGGCAGCGGGAACAAGTTGGTGACAGTTGGATCTAGTAACTACCAGCAA AGCTTCGTTCCTAGCCCGGGGGCACGTCCCCAGGTGAACGGGCAGAGTGGCCGGATCGAT TTTCATTGGCTGATGCTCAATCCAAACGACACTGTCACATTCAGTTTTAACGGAGCCTTT ATCGCCCCTGATAGAGCCTCATTCCTTAGGGGAAAAAGTATGGGAATCCAGTCTGGTGTA CAGGTGGATGCCAACTGTGAAGGTGACTGTTATCATTCAGGTGGAACCATCATATCAAAC CTGCCCTTCCAAAATATTGACTCAAGAGCAGTGGGCAAGTGCCCCCGATATGTGAAGCAG CGATCCCTGCTGCTCGCAACTGGCATGAAGAATGTCCCGGAAATCCCTAAGGGGCGGGGC CTTTTCGGGGCAATCGCAGGCTTCATCGAAAATGGATGGGAGGGCCTGATCGACGGATGG TACGGTTTCCGGCATCAGAATGCTCAGGGGGAGGGGACCGCGGCTGACTATAAGTCGACA CAATCTGCCATAGATCAGATCACGGGAAAACTGAACAGACTGATAGAGAAGACTAATCAG CAGTTCGAACTGATCGATAACGAGTTCAATGAGGTTGAAAAGCAAATCGGGAACGTAATC AACTGGACACGAGACAGCATTACTGAGGTGTGGTCCTACAATGCGGAATTGCTGGTGGCT ATGGAAAATCAACACACAATCGATCTTGCCGATTCAGAGATGGACAAGCTTTACGAGAGA GTAAAGCGACAACTGCGCGAGAATGCTGAGGAGGACGGGACTGGGTGCTTCGAGATCTTT CACAAGTGTGACGACGACTGCATGGCCTCTATCCGGAATAATACTTATGACCATAGCAAA TATAGAGAGGAGGCCATGCAAAACCGGATCCAGATTGATCCAGTCAAGCTCTCCAGCGGT TATAAGGATGTGATTTTGTGGTTCAGTTTTGGCGCTTCATGCTTCATACTCTTGGCCATC GTGATGGGCCTGGTGTTTATTTGTGTGAAGAACGGAAACATGCGGTGTACAATTTGCATC 583 ATGAATACCCAGATCCTCGTTTTCGCTCTGATCGCAATCATTCCCACAAACGCAGATAAA ATCTGTCTGGGGCATCACGCTGTGAGCAACGGCACAAAAGTTAACACCTTAACCGAGCGC GGCGTGGAGGTGGTTAATGCTACCGAGACCGTCGAACGGACCAATATCCCCAGGATCTGT AGTAAAGGCAAGAAGACAGTCGACCTGGGGCAGTGTGGGCTCCTCGGGACTATCACAGGA CCCCCTCAGTGTGATCAGTTCCTCGAGTTCTCAGCGGACCTTATTATAGAACGCCGAGAG GGTTCTGATGTGTGTTACCCCGGCAAATTTGTGAACGAGGAGGCTCTGAGGCAAATTCTG CGCGAAAGCGGCGGCATTGAAAAGGAAGCTATGGGGTTTACATACTCCGGAATAAGAGCC AATGGCGCGACTTCTGCTTGTCGAAGGTCCGGAAGCTCCTTTTATGCGGAAATGAAATGG CTATTGAGCAATACCGACAATGCTGCCTTCCCCCAGATGACCAAGAGTTATAAAAATACC CGAAAAAGCCCCGCGCTTATCGTTTGGGGCATCCATCATTCTGTTTCTACAGCCGAACAG ACTAAGCTTTATGGCAGCGGGAATAAGCTCGTGACCGTCGGCTCAAGTAACTATCAGCAG TCATTCGTGCCTTCCCCGGGGGCTAGACCTCAAGTGAATGGATTATCCGGACGAATCGAC TTCCATTGGTTGATGTTAAACCCTAATGATACTGTGACCTTCTCCTTCAACGGGGCCTTC ATTGCTCCAGATCGTGCTAGTTTCCTGCGGGGCAAGTCCATGGGTATTCAATCCGGAGTC CAGGTCGACGCAAACTGTGAGGGGGATTGCTACCACTCCGGAGGCACAATTATTTCTAAT CTGCCATTTCAGAACATTGACTCCCGCGCCGTGGGGAAATGTCCAAGGTATGTGAAACAA CGGAGCCTACTGCTCGCCACCGGAATGAAGAACGTTCCTGAAATACCTAAAGGTCGGGGT TTGTTTGGGGCTATAGCCGGCTTCATAGAAAACGGATGGGAAGGCCTGATCGATGGCTGG TATGGCTTTAGGCATCAAAATGCACAGGGGGAGGGCACTGCGGCTGACTATAAGAGCACC CAGTCAGCGATTGACCAGATTACTGGCAAGCTGAATAGACTTATAGAAAAGACAAATCAG CAATTCGAGCTGATAGACAACGAATTCAATGAGGTGGAGAAACAAATTGGTAACGTCATT AACTGGACTCGTGACTCTATTACGGAAGTGTGGAGTTACAATGCTGAGCTCCTCGTCGCC ATGGAAAACCAACACACTATAGATTTGGCCGATAGCGAGATGGACAAGCTGTACGAGAGG GTAAAACGCCAGTTGAGAGAAAACGCCGAGGAAGATGGCACCGGTTGCTTTGAGATTTTC CACAAGTGCGATGATGACTGCATGGCAAGCATCAGAAATAACACATACGATCATAGTAAA TACAGGGAGGAAGCCATGCAAAACCGCATTCAGATCGATCCCGTCAAGCTCTCTTCGGGG TACAAAGATGTCATCCTTTGGTTCTCATTCGGCGCATCTTGCTTTATCCTGCTGGCTATA GTGATGGGGCTCGTGTTTATTTGCGTCAAAAATGGAAACATGCGCTGTACCATCTGTATT 584 ATGAATACTCAGATCCTGGTGTTTGCGCTCATTGCGATCATCCCAACCAACGCCGACAAA ATATGTCTGGGACATCACGCCGTTTCCAACGGGACGAAGGTGAACACGTTGACAGAGCGC GGAGTGGAGGTCGTGAATGCTACTGAGACCGTGGAGAGGACTAATATCCCGAGGATCTGC AGTAAGGGCAAGAAGACTGTCGACTTAGGACAGTGTGGCCTGTTAGGCACAATCACAGGC CCCCCTCAATGTGACCAATTTCTGGAGTTTTCTGCCGACCTCATAATCGAGCGCAGGGAA GGCTCCGACGTGTGCTATCCGGGAAAGTTCGTCAACGAGGAAGCCCTCAGACAGATCCTT CGCGAATCCGGCGGCATAGATAAGGAAGCTATGGGTTTCACATATTCAGGAATCCGCACG AATGGCGCAACTTCCGCTTGCCGGCGATCAGGATCCTCTTTCTACGCAGAGATGAAGTGG CTGCTGAGCAATACCGACAATGCCGCCTTCCCCCAAATGACAAAGTCATACAAGAATACT CGTAAATCACCTGCCCTGATTGTGTGGGGAATCCATCACTCAGTGTCCACAGCGGAGCAG ACCAAGCTGTACGGAAGCGGTAACAAGCTTGTTACCGTTGGCTCTAGCAATTATCAGCAG AGCTTTGTTCCTTCACCTGGAGCCAGACCTCAAGTAAATGGGCAAAGCGGTAGAATCGAC TTTCACTGGCTGATGCTGAATCCCAATGACACAGTCACCTTTTCGTTTAACGGCGCGTTT ATAGCACCCGATAGGGCCAGTTTTTTGAGAGGAAAGTCAATGGGAATCCAAAGCGGCGTG CAAGTCGATGCCAATTGTGAGGGCGACTGTTACCATAGTGGGGGAACCATTATAAGTAAT TTACCCTTTCAGAATATTGACTCAAGGGCTGTGGGAAAATGTCCCAGGTATGTCAAGCAG AGAAGCCTGCTGCTGGCCACCGGTATGAAGAACGTACCCGAGATTCCAAAAGGCAGAGGA CTGTTTGGAGCAATTGCTGGGTTCATCGAGAACGGGTGGGAGGGGCTTATTGATGGCTGG TACGGATTTAGACATCAAAATGCACAGGGGGAAGGCACTGCCGCTGATTATAAAAGTACG CAGTCCGCGATAGACCAGATTACCGGAAAGTTGAACCGGCTGATCGAGAAAACTAATCAG CAGTTTGAGTTGATCGACAACGAATTTAACGAGGTGGAGAAACAAATCGGCAATGTGATT AACTGGACTAGAGACTCCATTACCGAGGTGTGGTCATATAACGCCGAATTGCTCGTGGCC ATGGAAAACCAGCACACCATCGATCTCGCTGATAGCGAGATGGACAAACTCTACGAAAGG GTCAAGAGACAACTCCGAGAGAACGCCGAGGAAGACGGGACTGGGTGTTTTGAGATCTTT CATAAATGTGATGACGACTGTATGGCTTCTATCCGGAATAACACATACGACCACTCCAAA TATCGGGAGGAAGCTATGCAAAATCGTATTCAAATTGATCCCGTCAAGCTGAGCTCCGGG TATAAGGACGTTATCCTCTGGTTCTCCTTTGGCGCTTCCTGTTTCATCCTTCTGGCTATT GTCATGGGGCTCGTTTTCATATGCGTTAAGAACGGGAATATGCGGTGTACGATCTGTATA 585 ATGAACACACAGATATTGGTGTTTGCTTTGATTGCAATCATTCCTACAAACGCGGATAAA ATCTGCCTGGGCCACCATGCTGTGAGTAACGGCACCAAAGTGAATACTTTAACTGAACGC GGTGTCGAGGTTGTGAACGCGACTGAAACGGTGGAGCGCACGAATATTCCCCGGATCTGC AGCAAAGGCAAAAAGACTGTCGACCTTGGTCAGTGCGGGCTACTTGGGACTATCACTGGA CCCCCACAGTGTGATCAATTCCTGGAATTTTCAGCCGATTTGATTATTGAGCGGAGAGAG GGATCCGACGTGTGCTATCCAGGCAAGTTTGTGAACGAGGAGGCATTGCGGCAGATTCTC AGGGAATCTGGAGGCATTGATAAGGAAGCTATGGGTTTCACCTATAGCGGTATCCGGACC AACGGAGCTACCAGCGCGTGCCGGAGGAGCGGTAGCTCCTTTTACGCGGAGATGAAGTGG TTGCTCTCTAACACGGACAACGCCGCCTTCCCACAGATGACCAAGAGCTACAAGAACACC CGCAAATCACCTGCCTTAATTGTGTGGGGCATTCATCATAGTGTCTCTACGGCCGAGCAG ACAAAACTGTATGGATCTGGCAATAAGCTTGTCACCGTCGGCAGCTCCAATTACCAGCAG TCTTTCGTACCCAGTCCCGGTGCAAGGCCACAGGTCAACGGACAGTCGGGGCGGATTGAC TTCCACTGGCTGATGCTCAACCCTAATGATACTGTAACCTTCAGCTTCAATGGCGCATTC ATAGCTCCCGATCGGGCATCATTCCTGCGAGGTAAATCTATGGGGATCCAGTCCGGCGTG CAGGTGGATGCCAACTGCGAGGGCGATTGCTATCACAGTGGTGGGACAATCATCTCTAAT TTACCCTTCCAGAATATTGATAGCCGAGCTGTGGGGAAATGCCCAAGGTACGTCAAGCAG CGTTCGCTTCTGTTAGCCACTGGCATGAAAAATGTGCCAGAGATACCCAAAGGCAGGGGG TTATTTGGAGCAATTGCCGGTTTTATTGAAAATGGCTGGGAGGGACTCATCGACGGCTGG TATGGCTTCAGACACCAAAATGCCCAGGGTGAAGGTACCGCCGCCGACTACAAGTCCACT CAAAGTGCAATTGACCAAATAACTGGAAAGCTGAACCGGCTGATCGAAAAGACAAATCAG CAGTTTGAGTTAATCGATAACGAGTTCAACGAGGTCGAGAAGCAGATTGGAAATGTCATT AACTGGACAAGGGATTCCATCACTGAGGTGTGGAGCTACAACGCCGAGCTGCTCGTCGCA ATGGAGAACCAGCATACTATTGACCTGGCAGACTCTGAAATGGATAAATTATACGAACGC GTGAAACGCCAGCTCAGAGAAAATGCTGAAGAGGACGGGACCGGTTGTTTTGAGATTTTT CACAAGTGCGACGACGATTGCATGGCCTCCATTAGGAACAATACATACGACCATAGTAAG TATCGAGAGGAAGCCATGCAGAACAGGATACAGATAGACCCTGTTAAACTGTCCTCCGGG TACAAGGATGTGATCCTTTGGTTTTCTTTTGGGGCATCCTGCTTTATTCTGCTGGCAATC GTCATGGGCCTTGTTTTTATCTGCGTAAAGAATGGAAATATGAGATGCACAATCTGTATC 586 ATGAACACCCAGATCCTTGTATTCGCATTAATAGCTATCATTCCAACAAACGCGGACAAA ATTTGCCTGGGGCACCATGCAGTCTCCAACGGCACTAAGGTGAATACGCTCACCGAGCGG GGCGTGGAGGTTGTTAATGCGACGGAGACGGTTGAGCGGACGAATATCCCCCGAATTTGT TCGAAGGGAAAACGGACAGTGGACCTGGGTCAGTGTGGGTTGCTGGGTACCATTACAGGC CCCCCCCAGTGTGATCAGTTTCTGGAATTTTCCGCCGACCTTATTATCGAGCGGAGGGAA GGGTCCGATGTCTGTTACCCAGGGAAGTTCGTTAACGAGGAGGCTTTGCGCCAGATACTC CGGGAGAGTGGTGGTATTGACAAGGAGGCCATGGGGTTCACCTACAGCGGCATCAGGACT AATGGAGCCACCTCGGCCTGTAGAAGAAGTGGATCTTCTTTCTATGCCGAGATGAAATGG TTGCTATCTAACACTGACAACGCCGCCTTTCCACAGATGACTAAAAGTTACAAAAATACA CGGAAAAGCCCAGCCTTAATAGTCTGGGGCATCCATCATAGTGTGTCCACCGCCGAACAG ACTAAACTATATGGGTCCGGAAGCAAGCTTGTGACGGTGGGCTCTTCCAACTACCAGCAG AGTTTTGTGCCCTCCCCCGGAGCACGGCCTCAGGTCAACGGCTTGAGCGGACGGATCGAC TTTCATTGGTTAATGCTGAATCCAAATGATACAGTAACATTTTCATTTAATGGCGCCTTC ATTGCTCCAGACAGAGCTAGTTTCTTACGGGGCAAATCAATGGGCATCCAGAGCGGGGTT CAGGTGGATGCCAACTGTGAAGGAGATTGTTATCACAGCGGCGGGACTATCATTTCTAAT CTCCCATTTCAGAATATCGATTCACGGGCAGTTGGCAAGTGCCCGAGATACGTCAAGCAG CGATCTCTCCTTCTCGCAACCGGAATGAAAAACGTCCCAGAGATTCCTAAAGGCAGGGGC CTGTTCGGCGCCATCGCCGGATTTATTGAGAACGGGTGGGAGGGGCTGATAGATGGCTGG TACGGCTTTCGGCATCAGAATGCACAGGGCGAGGGTACGGCTGCGGACTACAAAAGTACT CAAAGCGCAATCGACCAGATTACAGGAAAGCTGAACCGGTTAATTGAAAAGACAAACCAG CAATTCGAGCTCATCGACAATGAGTTTAATGAAGTGGAGAAGCAGATCGGCAATGTAATC AACTGGACCAGAGATAGTATCACTGAAGTGTGGTCCTACAACGCCGAGCTTCTGGTGGCT ATGGAGAACCAGCATACTATCGATCTTGCGGATAGCGAGATGGATAAGCTGTACGAGCGT GTTAAGCGACAGCTAAGAGAGAACGCGGAGGAGGACGGTACTGGGTGTTTCGAAATTTTT CACAAGTGCGATGACGATTGTATGGCGTCTATCCGCAATAATACTTATGATCATAGTAAG TATCGGGAAGAAGCTATGCAGAACCGCATCCAAATCGACCCCGTGAAGCTTTCAAGCGGT TACAAAGACGTTATCTTGTGGTTCAGCTTCGGGGCGTCTTGCTTTATCCTGCTGGCGATT GTAATGGGCTTGGTCTTTATCTGTGTGAAGTCCAGAAATATGAGATGCACCATTTGTATC 587 ATGAATACCCAAATCCTCGTGTTCGCTTTAATCGCAATCATCCCGACCAATGCCGACAAG ATCTGCCTGGGTCACCACGCTGTCTCCAACGGCACTAAGGTGAACACCTTAACAGAGAGA GGCGTGGAAGTAGTTAATGCTACCGAAACCGTGGAAAGGACCAACATTCCGCGGATATGT TCTAAGGGAAAACGCACCGTAGATCTCGGCCAGTGTGGACTGCTGGGCACAATCACCGGT CCTCCACAATGTGATCAGTTTCTTGAGTTCTCGGCCGACCTCATCATCGAAAGGAGGGAA GGATCTGATGTGTGTTATCCCGGGAAGTTCGTGAAAGAAGAGGCCCTGCGTCAGATATTG CGAGAGAGTGGCGGGATAGATAAGGAAGCAATGGGCTTCACATACAGCGGCATCAGAACA AATGGCGCGACATCCGCCTGTAGAAGGTCTGGGTCTAGCTTCTACGCAGAGATGAAATGG CTGCTCAGTAACACGGACAATGCGGCCTTCCCCCAGATGACTAAAAGCTATAAAAATACA AGGAAGAGCCCCGCCTTGATAGTGTGGGGAATCCATCATAGTGTGAGTACCGCTGAACAG ACGAAGCTATACGGATCAGGCAACAAGCTGGTTACTGTCGGCAGTTCTAACTACCAGCAA TCCTTTGTGCCTTCTCCCGGCGCCCGCCCACAAGTGAATGGACTATCTGGCAGAATTGAT TTCCACTGGCTGATGCTGAACCCCAATGACACTGTGACTTTCAGCTTTAACGGAGCCTTT ATCGCCCCCGATAGAGCCAGTTTCCTGAGGGGCAAATCCATGGGCATCCAGTCAGGCGTG CAGGTCGATGCCAACTGCGAGGGAGATTGTTACCATTCGGGTGGCACCATAATTAGTAAC TTACCATTCCAGAATATTGACAGCAGAGCCGTTGGGAAATGCCCCAGGTATGTCAAGCAG AGGTCCCTACTACTGGCCACAGGCATGAAGAATGTTCCTGAAATTCCTAAAGGCCGTGGT CTTTTCGGAGCAATCGCAGGATTCATCGAAAACGGCTGGGAAGGACTGATTGATGGGTGG TATGGTTTTAGGCACCAAAATGCACAGGGCGAGGGCACAGCTGCAGATTACAAGAGCACT CAGTCAGCTATTGATCAGATTACCGGAAAGCTTAACAGGCTCATCGAAAAGACTAATCAG CAGTTTGAACTGATCGACAACGAATTCAACGAAGTAGAGAAACAGATTGGGAACGTGATT AATTGGACCCGAGACTCTATCACAGAGGTGTGGAGTTACAACGCAGAGTTGCTGGTAGCA ATGGAAAACCAGCACACAATCGATCTCGCAGACAGTGAGATGGATAAACTTTACGAAAGG GTCAAACGTCAGTTAAGAGAGAACGCGGAAGAGGATGGCACCGGTTGCTTTGAAATTTTC CACAAATGCGATGACGACTGCATGGCGTCTATCAGAAATAACACTTACGACCATAGTAAG TATCGGGAGGAGGCTATGCAGAACCGAATTCAGATCGATCCAGTAAAGCTCAGCAGCGGC TACAAGGACGTCATCCTTTGGTTCTCTTTCGGGGCCAGTTGCTTCATCCTTCTCGCTATA GTCATGGGCCTCGTGTTTATCTGCGTAAAAAATGGGAACATGAGGTGCACCATTTGCATA 588 ATGAATACACAGATATTGGTCTTCGCTCTCATCGCTATCATTCCCACCAACGCTGACAAA ATCTGTTTAGGCCACCATGCCGTATCCAATGGCACTAAGGTCAACACACTTACTGAGCGA GGCGTAGAGGTCGTCAACGCTACAGAAACTGTTGAGCGAACCAACATCCCCAGGATTTGC TCTAAGGGGAAAAAGACTGTAGACCTTGGGCAGTGTGGCCTGCTGGGGACTATCACCGGG CCACCTCAATGTGACCAATTTCTGGAGTTCTCAGCTGATCTGATTATCGAGAGGCGCGAG GGATCTGATGTCTGTTACCCAGGTAAGTTCGTCAATGAGGAGGCGCTCCGCCAGATCCTC CGCGAGAGTGGCGGGATCGATAAAGAGGCCATGGGCTTCACTTACTCCGGCATCAGGACC AATGGCGCTACATCCGCCTGTAGACGGAGCGGATCCAGCTTTTACGCCGAAATGAAGTGG CTGCTGTCCAACACAGACAACGCTGCTTTTCCACAGATGACAAAGTCTTATAAAAATACC CGCAAATCTCCTGCCCTGATTGTGTGGGGCATTCACCACTCAGTGTCCACTGCCGAGCAG ACTAAGTTGTACGGAAGTGGCAACAAGCTGGTGACGGTCGGCTCTTCAAACTATCAACAG AGCTTTGTACCTTCCCCAGGGGCCCGGCCACAGGTGAACGGGCAGTCAGGAAGGATTGAT TTCCACTGGCTGATGCTGAATCCAAATGATACTGTCACCTTCAGCTTTAATGGAGCTTTT ATTGCCCCGGATCGCGCATCCTTCCTGCGCGGGAAGAGTATGGGGATCCAGTCCGGGGTA CAAGTCGACGCTAACTGCGAAGGCGATTGCTACCATAGCGGAGGAACCATCATTAGTAAC CTCCCCTTTCAGAATATTGATTCCCGTGCCGTTGGGAAATGTCCCAGATACGTCAAGCAG AGGTCCTTGCTGCTCGCAACCGGCATGAAGAATGTGCCAGAGATTCCAAAGGGGAGAGGT CTTTTCGGTGCTATCGCCGGCTTTATCGAGAACGGCTGGGAAGGGCTGATCGATGGCTGG TACGGATTCCGGCATCAAAACGCGCAGGGAGAGGGAACTGCGGCCGACTACAAGTCAACT CAGTCTGCCATCGATCAGATTACTGGTAAGCTTAACCGTCTCATCGAGAAAACCAACCAA CAATTTGAATTAATTGATAACGAGTTTAACGAAGTGGAGAAGCAAATTGGGAATGTCATA AACTGGACACGGGATTCTATCACCGAGGTATGGTCTTACAACGCGGAGTTGCTGGTCGCC ATGGAGAACCAACATACCATCGATCTGGCTGACAGTGAAATGGACAAGCTGTATGAGCGG GTGAAACGGCAGCTCCGGGAGAATGCAGAGGAAGACGGTACTGGCTGTTTCGAGATCTTC CATAAGTGCGACGATGACTGTATGGCCTCGATTAGGAACAACACCTATGATCACAGCAAG TATCGCGAGGAAGCGATGCAGAACCGGATTCAGATCGACCCAGTTAAACTCTCGTCGGGC TACAAGGATGTAATCCTGTGGTTTAGCTTCGGAGCGTCGTGTTTCATCTTGTTGGCGATA GTAATGGGCCTTGTTTTTATCTGCGTGAAGAACGGAAATATGAGATGCACTATCTGTATT 589 ATGAACACGCAGATCCTAGTGTTCGCACTTATCGCCATCATCCCTACCAATGCTGACAAA ATTTGCCTGGGACATCATGCGGTTTCTAATGGAACCAAGGTGAATACCCTAACAGAACGG GGGGTGGAAGTTGTCAATGCCACAGAAACGGTTGAGCGTACTAACATTCCCCGCATTTGC TCCAAAGGAAAAAAAACTGTGGATCTGGGCCAGTGTGGACTTCTGGGCACTATTACCGGC CCTCCTCAGTGCGACCAGTTCCTGGAGTTCTCTGCGGACCTTATTATTGAGAGACGTGAG GGATCTGATGTGTGTTATCCAGGGAAGTTCGTAAACGAAGAGGCTCTTAGACAAATCCTG CGGAAGAGCGGTGGCATAGATAAAGAGGCAATGGGGTTTACATACAGCGGCATAAGGACC AACGGCGCCACATCCACTTGCAGGCGGTCCGGGTCGTCATTTTACGCCGAGATGAAATGG TTGTTAAGTAATACAGACAACGCAGCCTTTCCGCAGATGACTAAATCTTATAAAAACACA CGAAAATCTCCGGCGATCATTGTATGGGGCATACACCACAGTGTTAGCACTGCCGAGCAG ACGAAACTATATGGCTCCGGAAATAAACTGGTCACCGTAGGATCCTCCAACTACCAGCAG AGCTTCGTGCCCTCGCCTGGCGCACGGCCACAAGTTAATGGTCTCAGCGGTCGGATTGAC TTTCACTGGCTCATGCTTAATCCTAATGACACAGTAACCTTCTCCTTTAACGGCGCCTTC ATAGCTCCCGACAGGGCATGTTTTCTGCGCGGGAAGAGTATGGGGATCCAGTCCGGGGTC CAGGTAGATGCAGACTGCGAAGGGGACTGCTACCACAGTGGGGGTACCATCATTAGTAAC CTTCCCTTTCAGAATATTGACAGCAGGGCCGTCGGGAAGTGCCCCCGCTACGTGAAGCAG CGGTCTTTGCTCCTGGCTACCGGTATGAAGAACGTGCCCGAGATACCAAAAGGCAGGGGG CTCTTTGGTGCCATCGCCGGCTTTATCGAAAATGGATGGGAGGGCCTCATCGACGGTTGG TACGGTTTCAGGCACCAGAATGCCCAGGGGGAAGGAACAGCTGCAGATTACAAGTCAACC CAGTCTGCTATTGACCAGATAACAGGGAAACTGAACCGATTAATTGAGAAAACTAATCAA CAGTTCGAGCTGATTGATAACGAGTTTAACGAGGTGGAACGCCAAATCGGGAACGTGATT AACTGGACAAGGGATTCAATCACAGAGGTTTGGAGTTATAATGCCGAACTGCTGGTCGCC ATGGAGAACCAGCACACTATCGATCTAGCTGATTCTGAGATGGACAAGCTCTATGAGCGC GTCAAGCGTCAGCTCCGCGAAAACGCTGAAGAAGATGGCACTGGCTGTTTCGAGATCTTC CACAAGTGTGACGACGACTGCATGGCCTCCATAAGGAATAACACTTATGATCACAGCAAG TATCGAGAGGAGGCCATGCAGAACCGCATTCAGATTGATCCCGTTAAGTTAAGTTCTGGG TATAAAGATGTCATTCTTTGGTTCTCTTTTGGTGCTTCATGTTTTATACTGCTGGCTATC GTCATGGGACTCGTGTTCATCTGCGTCAAAAATGGGAATATGCGGTGTACCATATGCATT 590 ATGAATACGCAGATCCTGGTGTTCGCTCTAATCGCTATTATCCCTACAAACGCAGATAAG ATCTGTTTAGGCCACCATGCAGTTTCTAATGGCACTAAGGTCAACACTCTCACTGAACGC GGGGTGGAGGTAGTCAACGCTACAGAGACAGTTGAACGAACAAACATCCCCAGGATTTGC TCTAAGGGTAAAAAAACAGTGGACCTGGGACAGTGCGGACTGCTCGGGACCATTACTGGG CCACCTCAGTGTGACCAGTTCTTGGAGTTTTCCGCCGATCTAATCATCGAAAGACGAGAA GGATCCGATGTGTGCTATCCTGGCAAGTTTGTGAATGAGGAAGCACTGCGGCAGATCTTG CGGGAGTCTGGCGGAATTGATAAGGAAGCAATGGGTTTTACCTACTCCGGTATTCGGACA AATGGAGCTACATCCGCATGTCGGCGGTCCGGAAGCAGTTTCTACGCCGAGATGAAGTGG CTATTGTCAAACACAGATAACGCTGCCTTCCCCCAGATGACTAAGAGCTATAAGAACACC CGGAAGAGCCCTGCCCTGATCGTCTGGGGCATTCATCATTCGGTCAGTACAGCCGAACAA ACTAAGTTGTACGGCTCCGGAAACAAGTTGGTTACAGTGGGGTCTTCCAACTACCAGCAG AGCTTTGTACCTTCCCCCGGAGCCCGACCCCAGGTCAACGGCCAGTCTGGAAGAATTGAT TTTCATTGGCTAATGCTGAATCCTAATGATACTGTGACATTTTCATTCAATGGAGCCTTC ATAGCACCTGATAGGGCCTCTTTCCTGCGGGGAAAAAGCATGGGTATTCAGAGTGGCGTT CAGGTGGATGCTAATTGCGAGGGGGACTGCTATCATAGTGGTGGGACCATTATTAGCAAC CTCCCCTTTCAGAATATAGATAGCAGGGCTGTCGGCAAATGTCCAAGGTACGTTAAGCAG CGGAGTCTACTGTTGGCCACCGGTATGAAAAACGTCCCCGAGATCCCTAAGGGACGCGGC CTGTTCGGCGCCATCGCCGGATTTATCGAGAACGGGTGGGAAGGCTTGATCGATGGGTGG TATGGATTCCGACATCAGAACGCCCAGGGCGAAGGTACTGCTGCCGACTATAAATCTACG CAGAGCGCAATAGACCAGATTACGGGGAAACTGAACAGGCTGATCGAGAAGACCAATCAG CAGTTTGAGCTGATTGACAATGAATTCAACGAAGTTGAGAAACAGATCGGTAACGTGATA AATTGGACTAGAGATAGTATCACCGAGGTATGGAGCTACAACGCCGAGCTGCTTGTCGCT ATGGAAAACCAGCACACCATCGACCTTGCTGACAGTGAGATGGATAAACTCTATGAACGA GTGAAGAGACAGTTGCGGGAAAACGCCGAAGAGGACGGTACCGGGTGCTTTGAGATATTT CACAAGTGCGATGATGACTGTATGGCTAGTATCCGCAATAATACATATGACCATAGTAAG TACAGAGAAGAAGCCATGCAAAACAGAATACAAATTGACCCCGTGAAGTTAAGCTCAGGA TACAAAGATGTCATCCTTTGGTTCTCCTTCGGCGCATCATGCTTTATACTTCTCGCAATC GTGATGGGTCTGGTTTTTATATGCGTCAAGAACGGCAATATGCGCTGTACGATCTGTATT 591 ATGAACACCCAGATTCTGGTTTTTGCATTGATCGCCATTATTCCGACTAATGCCGACAAA ATCTGTTTGGGACACCACGCCGTGAGCAACGGCACGAAAGTCAACACACTCACAGAACGA GGCGTGGAAGTTGTCAACGCAACCGAGACGGTTGAGCGCACCAACATCCCAAGGATCTGC TCTAAGGGCAAGAAGACCGTGGACCTTGGGCAGTGTGGCCTGCTGGGGACAATAACCGGT CCACCACAATGTGATCAATTCCTGGAGTTTTCAGCCGACCTCATCATAGAACGCCGGGAA GGTTCTGACGTGTGCTACCCGGGCAAATTTGTCAACGAGGAGGCTCTCAGGCAGATCCTG AGGGAGTCAGGCGGAATTGACAAGGAAGCCATGGGTTTCACGTACAGCGGTATTCGGACC AATGGGGCTACATCAGCCTGTCGCAGATCTGGAAGTTCTTTTTACGCTGAAATGAAGTGG CTGCTGTCAAATACCGATAACGCTGCATTTCCCCAGATGACAAAAAGTTATAAGAATACC AGGAAGTCCCCCGCCTTGATCGTGTGGGGCATACACCACTCAGTGAGTACAGCCGAGCAG ACCAAGTTGTATGGATCGGGTAACAAACTAGTCACCGTGGGCTCCAGCAATTATCAGCAG AGTTTTGTCCCCAGCCCCGGGGCTAGACCGCAAGTCAATGGTCAGTCCGGCCGTATCGAT TTTCACTGGCTGATGCTAAATCCCAATGACACTGTAACCTTTTCCTTTAATGGGGCATTC ATTGCACCCGACAGGGCATCCTTTTTGCGGGGTAAGAGTATGGGTATCCAGAGTGGCGTC CAGGTGGATGCAAACTGCGAGGGTGACTGCTACCATTCAGGAGGCACGATTATATCAAAT CTGCCCTTTCAGAACATTGACAGTCGCGCCGTTGGCAAATGTCCAAGGTACGTGAAGCAG AGAAGCCTCCTGCTCGCCACTGGCATGAAAAATGTGCCCGAGATTCCCAAAGGCCGGGGT CTTTTTGGCGCAATAGCTGGTTTTATCGAGAATGGTTGGGAAGGACTCATCGACGGCTGG TACGGATTTCGGCACCAAAACGCCCAAGGGGAAGGAACCGCCGCAGATTACAAGAGCACG CAGTCAGCTATCGACCAGATCACCGGCAAGCTTAATCGGCTTATTGAAAAAACCAATCAA CAATTCGAGCTGATTGACAATGAATTTAATGAAGTGGAGAAACAAATTGGGAACGTGATC AATTGGACCAGAGACAGCATAACTGAAGTGTGGAGTTATAACGCAGAACTGCTGGTCGCT ATGGAAAATCAACACACTATTGATCTGGCCGATAGCGAAATGGACAAGCTATACGAAAGG GTTAAACGGCAGCTTCGCGAGAACGCCGAGGAGGACGGCACCGGCTGCTTCGAGATTTTC CACAAGTGTGATGACGATTGTATGGCCTCCATCAGAAACAACACCTACGACCATAGCAAG TATAGAGAAGAAGCCATGCAGAATCGCATCCAGATCGACCCCGTTAAGCTTTCATCCGGC TATAAGGACGTTATCTTATGGTTCTCTTTTGGAGCATCATGCTTTATCCTCCTGGCTATC GTTATGGGCCTTGTTTTCATCTGCGTTAAAAACGGGAATATGCGCTGCACCATCTGTATT 592 ATGAATACACAGATCTTAGTGTTTGCTCTTATAGCAATCATACCCACAAACGCCGATAAG ATCTGTCTGGGGCACCATGCCGTGAGCAACGGAACTAAGGTTAACACATTAACTGAGAGA GGTGTGGAGGTAGTTAACGCGACCGAGACTGTAGAGCGGACTAATATCCCTCGCATTTGC AGTAAGGGCAAAAAGACCGTTGACCTTGGTCAGTGTGGGCTGCTTGGAACCATCACCGGA CCTCCTCAGTGTGACCAGTTCCTCGAATTTTCCGCTGACCTGATTATTGAGAGAAGGGAA GGGAGTGACGTGTGTTATCCTGGCAAATTCGTCAATGAAGAAGCGCTACGCCAGATCCTT AGAGAGAGTGGGGGAATCGATAAGGAGGCAATGGGCTTTACATACAGTGGCATAAGAACC AATGGCGCGACAAGTGCCTGCCGCCGGAGCGGCTCAAGTTTCTATGCTGAGATGAAATGG TTACTCAGTAATACTGATAATGCCGCATTTCCACAGATGACTAAATCTTATAAAAATACA CGGAAATCACCCGCACTGATTGTATGGGGTATCCACCACAGCGTCTCCACAGCGGAGCAA ACAAAACTGTACGGCAGTGGGAACAAATTGGTTACTGTTGGGTCCTCGAATTATCAGCAG TCTTTCGTCCCTAGCCCTGGAGCTCGCCCCCAAGTTAACGGTCAGAGCGGCAGGATAGAT TTCCACTGGTTAATGCTAAACCCTAATGACACCGTAACCTTTTCGTTTAATGGAGCATTC ATTGCGCCTGACCGCGCGAGCTTCTTAAGGGGAAAGTCAATGGGAATTCAATCTGGGGTC CAAGTCGACGCAAATTGTGAGGGCGACTGCTACCACTCAGGAGGAACTATCATCTCGAAC CTGCCTTTTCAAAACATCGATAGCAGAGCCGTTGGCAAGTGCCCTCGCTATGTGAAACAG CGCTCACTTCTCTTAGCGACGGGAATGAAGAACGTTCCGGAGATCCCAAAGGGTCGTGGC TTGTTTGGCGCAATAGCAGGGTTCATAGAGAACGGATGGGAAGGTCTGATTGACGGTTGG TATGGCTTCAGACACCAGAATGCTCAGGGAGAAGGAACCGCAGCCGATTATAAATCAACA CAGAGCGCCATAGATCAGATCACAGGAAAGTTAAATCGCCTGATCGAGAAGACGAATCAG CAGTTCGAGCTGATCGACAACGAGTTCAACGAAGTCGAGAAACAAATTGGCAACGTGATC AACTGGACGAGGGATAGCATTACGGAGGTGTGGTCTTATAACGCTGAACTACTTGTGGCA ATGGAGAACCAGCATACAATCGACCTCGCTGACTCAGAAATGGATAAGCTGTACGAGAGA GTTAAACGGCAGTTGAGAGAAAACGCAGAGGAGGATGGCACAGGCTGCTTTGAAATTTTT CACAAGTGCGATGATGACTGCATGGCTTCCATTCGGAACAATACGTATGACCACTCTAAA TACAGGGAAGAGGCCATGCAGAATCGCATCCAGATCGATCCTGTAAAGTTGTCCTCAGGC TATAAAGATGTGATCCTCTGGTTTTCCTTTGGGGCATCATGTTTCATTCTGCTCGCCATC GTGATGGGGCTGGTGTTCATTTGTGTTAAGAACGGGAATATGCGGTGCACTATCTGTATT 593 ATGAATACGCAGATACTCGTGTTTGCCCTGATCGCCATAATCCCTACGAACGCAGATAAG ATCTGCCTCGGACACCACGCTGTTAGCAACGGAACCAAGGTTAACACTTTGACGGAGAGG GGAGTGGAGGTCGTTAATGCCACCGAAACCGTGGAACGTACCAACATCCCCCGGATCTGT TCCAAAGGTAAAAAGACTGTCGATCTGGGACAGTGCGGCTTACTGGGAACTATTACTGGG CCCCCGCAGTGTGACCAATTCCTGGAATTCTCTGCAGATCTTATTATTGAGCGGAGGGAG GGGAGCGACGTCTGCTATCCGGGGAAGTTCGTCAACGAGGAGGCCTTGAGACAGATCCTG AGAGAATCTGGGGGCATCGATAAAGAAGCCATGGGATTTACTTATAGCGGCATAAGAACC AATGGCGCCACATCCGCCTGCCGTAGGAGTGGCTCAAGTTTTTATGCAGAAATGAAATGG CTACTCAGCAATACTGACAACGCTGCCTTCCCCCAGATGACAAAGAGCTATAAGAATACC AGGAAGTCACCAGCCCTGATCGTTTGGGGCATACACCATTCCGTATCTACCGCGGAGCAA ACAAAGCTTTATGGCTCTGGGAATAAGCTTGTAACTGTTGGCAGTAGTAATTATCAGCAG AGCTTTGTTCCATCCCCTGGCGCCCGGCCCCAGGTGAATGGTCAAAGCGGCAGGATAGAC TTTCACTGGCTGATGCTCAACCCCAACGATACTGTGACATTCTCCTTTAACGGAGCCTTC ATTGCTCCCGACCGCGCCTCTTTCCTCAGGGGCAAAAGTATGGGGATTCAGTCAGGTGTT CAGGTGGACGCAAACTGCGAAGGCGATTGCTACCACTCGGGGGGGACAATCATATCCAAC CTGCCCTTCCAGAACATTGACAGTCGCGCCGTGGGTAAATGCCCACGGTACGTGAAACAG CGGTCCCTGCTACTGGCTACTGGGATGAAAAACGTCCCTGAGATTCCCAAAGGCCGGGGA CTGTTTGGCGCTATCGCGGGGTTCATAGAGAATGGGTGGGAGGGCTTGATCGACGGGTGG TACGGTTTTAGACATCAGAACGCGCAAGGGGAGGGGACTGCTGCAGATTACAAGTCGACA CAGTCCGCAATCGACCAGATCACCGGTAAATTGAACCGGCTGATAGAAAAGACCAACCAG CAGTTTGAGTTGATAGACAATGAATTCAATGAGGTCGAAAAACAGATCGGTAATGTGATT AATTGGACTCGGGATTCAATTACGGAAGTATGGTCTTACAACGCGGAGTTGTTAGTTGCA ATGGAAAACCAGCACACGATCGATCTTGCAGACTCTGAAATGGATAAATTATACGAGCGG GTCAAACGCCAGCTTCGGGAAAACGCCGAAGAGGATGGTACTGGATGTTTTGAGATCTTT CATAAATGCGACGACGATTGTATGGCCAGCATTCGGAACAATACTTACGACCATTCAAAG TACCGGGAGGAAGCCATGCAGAATAGAATCCAGATTGATCCAGTGAAACTCAGCTCGGGA TACAAAGATGTGATTCTGTGGTTCTCCTTCGGGGCCTCTTGCTTCATACTGCTGGCTATC GTAATGGGGCTTGTCTTCATATGTGTGAAAAACGGGAATATGAGATGCACCATTTGTATC 594 ATGAATACTCAGATACTCGTTTTTGCTTTGATAGCCATCATTCCAACTAACGCTGACAAA ATCTGCCTAGGACACCATGCAGTGTCAAATGGCACAAAGGTGAATACTTTGACGGAGAGG GGCGTGGAGGTGGTGAACGCAACAGAGACAGTGGAGCGCACCAACATTCCACGCATTTGT AGTAAAGGAAAGAAGACAGTCGACCTCGGCCAGTGCGGGCTACTGGGTACGATTACTGGA CCCCCCCAGTGTGATCAGTTTCTTGAGTTTAGCGCGGATCTGATAATTGAGCGCCGGGAG GGTTCCGATGTCTGTTACCCCGGAAAGTTTGTGAACGAAGAAGCCCTTAGGCAAATCCTG CGCGAGAGCGGCGGAATTGAGAAGGAAGCTATGGGGTTCACGTATAGCGGTATTCGGGCT AACGGAGCCACTAGTGCATGTCGCCGCAGCGGCTCCTCATTCTACGCTGAGATGAAGTGG CTGCTGTCCAATACCGACAATGCTGCTTTTCCGCAGATGACTAAGTCATACAAAAACACT AGAAAGTCGCCCGCTTTGATTGTTTGGGGCATCCACCACAGCGTGAGTACAGCTGAGCAG ACAAAGCTATATGGTTCAGGGAATAAATTAGTTACCGTGGGCAGCTCTAACTACCAGCAG TCCTTTGTGCCCTCTCCCGGCGCTCGGCCTCAGGTAAATGGGCTTAGCGGCCGGATCGAC TTTCATTGGCTGATGCTCAACCCTAATGACACAGTGACGTTCTCTTTCAATGGCGCGTTC ATTGCCCCCGACAGGGCTTCTTTCCTACGGGGGAAAAGCATGGGTATTCAGTCAGGTGTT CAAGTAGACGCAAACTGTGAAGGAGACTGTTACCACAGCGGGGGCACAATCATTTCAAAT CTTCCTTTCCAGAACATAGATAGCCGGGCAGTCGGTAAATGCCCTCGGTATGTGAAACAA AGATCCCTGTTGCTAGCAACAGGCATGAAAAACGTCCCAGAGATCCCTAAGGGACGCGGA CTTTTCGGCGCGATCGCGGGATTTATCGAGAACGGCTGGGAAGGCCTAATCGATGGATGG TATGGGTTTAGGCATCAGAATGCTCAGGGGGAGGGAACGGCTGCAGATTATAAATCTACT CAGTCTGCTATCGACCAAATCACTGGGAAGCTCAATAGGCTGATTGAAAAAACAAATCAA CAGTTCGAGCTGATAGACAATGAGTTCAACGAGGTAGAGAAGCAGATAGGTAACGTAATT AATTGGACTCGCGACTCCATTACAGAAGTGTGGTCCTACAATGCTGAGCTGCTTGTGGCA ATGGAAAACCAGCACACCATAGACCTGGCTGATTCAGAAATGGATAAACTGTATGAGAGG GTGAAGAGGCAGCTCCGGGAAAACGCTGAGGAAGACGGCACAGGTTGCTTCGAAATTTTT CATAAGTGCGATGACGACTGTATGGCTTCAATTCGAAACAATACATACGACCACTCCAAG TATCGAGAGGAAGCCATGCAGAATCGTATCCAAATTGATCCCGTTAAACTATCATCCGGA TATAAAGACGTCATCTTGTGGTTTTCCTTCGGGGCCTCTTGTTTCATCCTCCTCGCAATC GTTATGGGATTGGTGTTTATCTGCGTGAAAAACGGCAACATGCGGTGCACAATATGCATT 595 ATGAACACCCAGATCTTGGTGTTCGCCCTCATTGCTATTATACCAACTAATGCGGACAAA ATCTGCCTTGGACACCATGCCGTATCCAATGGAACCAAGGTCAATACACTGACGGAGAGG GGAGTGGAAGTAGTGAACGCCACGGAAACAGTGGAAAGGACAAATATCCCTAGGATTTGC TCCAAAGGCAAAAGAACAGTGGACCTGGGGCAATGCGGGCTTTTGGGTACTATTACAGGA CCACCTCAGTGCGACCAATTCCTTGAGTTCAGCGCTGATCTGATTATAGAGAGGCGCGAG GGGAGTGATGTTTGCTACCCCGGTAAGTTCGTAAATGAGGAGGCTCTGCGGCAGATCTTA CGCGAAAGCGGGGGCATTGATAAGGAAGCTATGGGGTTTACCTACAGCGGCATTCGCACT AATGGCGCGACATCTGCCTGTCGCCGTTCCGGGTCATCTTTCTATGCAGAGATGAAATGG CTGCTCTCCAATACTGATAATGCTGCTTTCCCTCAAATGACAAAGTCTTACAAGAATACA AGGAAGTCTCCCGCACTGATTGTGTGGGGCATCCACCACAGCGTCTCAACCGCTGAGCAG ACTAAACTGTATGGTTCTGGGAACAAGCTCGTGACCGTCGGATCGTCTAATTATCAGCAG AGCTTCGTCCCATCACCTGGCGCCAGACCCCAAGTGAACGGTCTGTCCGGCAGAATTGAT TTCCACTGGCTGATGCTGAATCCCAATGACACGGTCACATTCTCATTTAATGGCGCATTC ATTGCCCCGGATAGAGCTTCCTTTCTCAGGGGCAAGTCTATGGGAATTCAGAGCGGTGTC CAGGTGGACGCGAATTGCGAAGGGGACTGCTATCACTCCGGCGGCACCATCATTTCTAAC CTCCCTTTTCAGAATATTGACAGTCGCGCCGTCGGGAAATGCCCTCGCTACGTGAAGCAG AGATCACTGCTCTTGGCCACAGGAATGAAGAACGTGCCCGAGATCCCGAAAGGGAGAGGG CTCTTCGGAGCCATCGCTGGGTTCATTGAAAACGGATGGGAAGGCCTGATAGACGGCTGG TACGGCTTCCGGCACCAAAACGCCCAGGGGGAAGGAACAGCCGCTGACTATAAATCTACA CAGAGCGCGATAGACCAGATCACCGGCAAATTAAATCGTCTCATCGAAAAAACAAATCAG CAGTTTGAGCTTATCGATAATGAATTCAACGAGGTTGAAAAGCAAATCGGGAATGTTATA AATTGGACCCGAGACTCCATTACCGAGGTGTGGAGCTATAACGCCGAGCTGTTGGTGGCC ATGGAGAACCAACATACAATTGATTTGGCCGACTCCGAGATGGACAAGCTGTATGAGCGG GTTAAACGGCAACTGCGTGAGAATGCAGAAGAAGACGGCACTGGCTGCTTCGAAATCTTC CACAAGTGCGATGATGATTGCATGGCTTCAATACGCAATAACACATACGATCACAGCAAA TACAGGGAGGAAGCTATGCAGAATCGCATCCAGATTGATCCAGTGAAGCTGTCATCCGGA TACAAAGATGTTATATTATGGTTCTCCTTTGGGGCTTCCTGTTTCATCCTGCTGGCAATC GTGATGGGCCTAGTGTTCATATGCGTCAAGAATGGAAACATGAGATGCACCATCTGTATC 596 ATGAATACCCAGATACTTGTATTTGCCCTTATCGCCATAATCCCCACTAACGCCGACAAG ATTTGTCTAGGGCACCATGCAGTATCTAATGGAACAAAAGTGAATACCCTCACAGAACGG GGTGTTGAAGTGGTTAATGCCACCGAAACAGTCGAGAGAACTAACATTCCCAGGATTTGT AGCAAGGGTAAGAAGACAGTTGACCTTGGGCAGTGTGGCTTACTTGGAACTATTACCGGC CCACCACAGTGCGATCAGTTTCTGGAGTTCAGCGCAGATCTCATTATTGAGAGAAGAGAA GGAAGCGACGTGTGCTACCCTGGCAAGTTCGTGAATGAGGAGGCCCTTCGGCAGATCCTT AGGGAGTCCGGAGGCATTGATAAGGAGGCTATGGGTTTTACCTATTCTGGCATTCGTACC AACGGGGCCACAAGTGCTTGTCGCCGCTCCGGTTCTTCCTTTTACGCTGAGATGAAATGG TTGCTCAGCAACACTGACAATGCTGCTTTCCCACAGATGACAAAATCCTACAAAAATACC AGAAAATCGCCCGCCTTGATTGTGTGGGGGATCCACCATAGTGTGTCTACCGCTGAGCAG ACCAAGCTGTATGGTTCCGGGAATAAGCTCGTGACCGTAGGTTCTTCCAATTATCAGCAG AGTTTCGTGCCTTCCCCCGGCGCCAGACCTCAGGTGAATGGCCAGAGCGGGAGAATAGAC TTCCATTGGCTCATGCTGAACCCTAACGATACAGTGACCTTCAGTTTCAACGGCGCCTTC ATCGCTCCAGACCGCGCCTCATTCCTTCGCGGCAAAAGCATGGGGATCCAGTCCGGGGTT CAAGTAGACGCCAACTGCGAGGGTGACTGCTATCACTCCGGAGGGACGATAATCAGCAAT CTTCCCTTCCAGAACATCGATAGCCGCGCCGTCGGTAAGTGCCCACGCTACGTTAAACAG CGCAGCCTGCTCTTGGCTACCGGCATGAAGAACGTCCCCGAAATCCCTAAGGGCCGGGGC CTGTTCGGGGCCATTGCGGGTTTTATTGAGAATGGCTGGGAGGGGCTGATAGACGGGTGG TACGGATTTAGACACCAGAATGCTCAGGGGGAAGGGACCGCTGCCGATTATAAGAGCACC CAGTCTGCTATTGACCAGATTACGGGTAAGCTGAACAGACTTATTGAAAAAACCAACCAG CAGTTTGAGCTTATCGACAATGAATTCAACGAAGTGGAGAAGCAGATCGGGAATGTCATC AACTGGACAAGAGATAGCATCACAGAGGTCTGGTCATATAACGCCGAACTGTTGGTGGCC ATGGAAAATCAACACACTATAGATCTAGCCGACTCTGAAATGGATAAGTTGTACGAGCGG GTAAAACGGCAGCTGCGGGAAAACGCTGAGGAAGATGGCACCGGATGCTTCGAGATTTTT CATAAATGCGATGACGACTGTATGGCCTCTATCAGGAATAATACATACGATCATAGTAAG TACCGGGAAGAAGCCATGCAGAACAGGATCCAGATAGATCCCGTTAAGCTGTCTAGCGGG TACAAGGATGTCATCTTATGGTTCAGCTTCGGCGCCAGCTGCTTCATCCTATTGGCCATT GTCATGGGACTAGTCTTTATCTGCGTGAAAAACGGTAATATGCGGTGTACTATCTGTATC 597 ATGAATACCCAGATCCTGGTTTTCGCGCTGATCGCAATCATACCTACTAACGCAGATAAG ATTTGCTTGGGACATCATGCCGTGTCCAACGGCACAAAAGTCAATACCCTCACAGAGAGG GGCGTTGAGGTGGTGAATGCTACCGAGACTGTGGAGAGGACCAATATTCCGAGAATTTGC TCAAAAGGAAAGCGTACAGTCGACCTGGGGCAATGTGGCCTACTCGGCACCATTACAGGG CCCCCCCAGTGTGACCAGTTTCTCGAATTTTCTGCTGACCTCATCATCGAGAGACGCGAG GGGTCCGACGTGTGTTACCCTGGCAAATTCGTTAATGAAGAAGCCCTAAGACAAATTCTA CGCGAGAGCGGAGGTATTGACAAAGAGGCTATGGGATTCACTTATTCTGGTATCCGCACC AACGGCGCTACCTCCGCCTGCCGGCGCTCCGGATCCAGCTTTTATGCTGAGATGAAATGG TTGCTGTCCAACACCGACAATGCTGCATTTCCTCAGATGACCAAATCTTATAAAAACACA AGAAAGAGTCCTGCGTTGATTGTGTGGGGAATACACCACTCAGTAAGCACTGCCGAACAG ACGAAGCTGTATGGTTCCGGAAACAAGCTCGTTACAGTGGGCAGTTCAAATTACCAGCAG AGCTTTGTTCCTTCCCCAGGGGAACGACCCCAAGTTAATGGACTGTCCGGGAGAATTGAT TTCCATTGGCTGATGCTGAACCCCAACGACACTGTGACGTTCTCCTTTAATGGGGCATTT ATCGCCCCGGATAGAGCTTCTTTTCTGAGAGGCAAGTCAATGGGGATCCAGTCAGGGGTG CAAGTCGATGCCAACTGCGAAGGAGATTGTTATCACTCAGGAGGCACGATTATTAGCAAT CTGCCCTTCCAGAATATTGATTCTCGCGCCGTGGGCAAATGTCCTCGATACGTGAAGCAG AGATCCCTGCTGCTGGCTACCGGCATGAAAAATGTACCAGAGATTCCAAAGGGGAGAGGA CTGTTCGGTGCCATCGCCGGTTTCATAGAAAATGGGTGGGAGGGCCTGATTGATGGCTGG TACGGTTTTAGGCACCAGAATGCTCAGGGAGAAGGGACCGCCGCAGATTATAAAAGCACT CAGTCTGCAATCGATCAGATAACAGGTAAACTGAACCGCCTGATTGAGAAGACAAACCAG CAGTTTGAACTGATCGATAATGAGTTTAATGAAGTGGAGAAGCAGATTGGCAACGTTATC AACTGGACACGGGACTCCATCACCGAAGTGTGGAGCTACAACGCTGAGCTGCTGGTAGCC ATGGAAAATCAGCACACAATCGATCTGGCTGACTCAGAAATGGACAAGCTCTATGAGAGG GTCAAAAGGCAACTAAGAGAAAATGCCGAGGAAGATGGGACCGGCTGTTTCGAGATATTT CACAAATGCGACGATGACTGCATGGCTAGCATTAGGAATAATACCTACGATCATAGCAAA TATCGGGAAGAAGCTATGCAGAACCGCATCCAAATAGATCCCGTCAAGTTGAGCTCTGGG TACAAGGATGTGATTCTGTGGTTCTCTTTCGGCGCCTCTTGCTTTATTCTGCTGGCAATC GTGATGGGTCTGGTGTTTATTTGTGTCAAAAACGGTAACATGCGCTGCACTATCTGCATA 598 ATGAATACACAGATTCTAGTGTTTGCCTTGATAGCTATAATCCCAACCAACGCGGACAAG ATCTGTCTCGGACACCATGCCGTGTCAAATGGTACTAAGGTGAATACACTGACCGAAAGA GGAGTGGAGGTCGTGAATGCGACAGAAACGGTTGAGCGAACCAACATTCCTAGGATCTGT AGTAAGGGAAAGCGAACTGTCGATCTGGGCCAGTGTGGACTCCTCGGGACCATTACAGGG CCTCCTCAGTGTGATCAGTTTTTGGAATTTTCCGCAGACTTGATAATCGAGAGGCGGGAA GGGTCTGACGTGTGCTACCCAGGCAAATTTGTAAATGAAGAGGCCCTAAGGCAGATCCTG AGGGAGAGTGGTGGAATCGATAAAGAAGCCATGGGATTTACATATTCAGGCATCAGGACC AACGGCGCAACATCAGCCTGCCGAAGATCGGGATCTTCATTCTACGCCGAGATGAAATGG TTGCTATCCAACACTGACAATGCCGCATTCCCCCAGATGACTAAAAGCTACAAAAACACC CGGAAGTCCCCAGCTCTCATCGTCTGGGGGATCCATCACAGTGTGTCCACCGCCGAGCAG ACCAAGCTGTATGGATCCGGCAGTAAACTGGTTACTGTGGGGTCATCTAATTACCAACAG AGTTTTGTGCCATCGCCTGGCGCCAGACCTCAAGTGAATGGACTGTCCGGTAGAATTGAT TTTCACTGGCTCATGCTGAACCCTAATGACACGGTTACCTTTTCTTTCAACGGAGCATTT ATAGCTCCGGATCGCGCCAGTTTTCTACGGGGGAAAAGCATGGGAATCCAGTCGGGTGTG CAGGTAGATGCTAACTGCGAAGGTGATTGCTACCACTCCGGTGGTACAATCATCAGCAAT CTGCCGTTCCAGAACATAGATAGTCGTGCAGTGGGTAAGTGCCCTAGGTACGTGAAACAA AGATCTCTGCTGCTTGCAACCGGTATGAAGAACGTGCCTGAGATTCCGAAAGGGCGCGGC TTATTCGGAGCTATAGCTGGATTCATCGAGAATGGATGGGAGGGCCTGATTGATGGTTGG TACGGGTTTCGACATCAGAACGCCCAGGGAGAGGGTACCGCTGCTGACTACAAGAGCACC CAATCCGCTATCGACCAGATAACTGGCAAGCTGAATAGACTGATTGAAAAGACAAATCAG CAATTTGAATTGATCGACAACGAATTCAACGAAGTGGAAAAGCAGATTGGTAACGTGATC AACTGGACCAGAGACTCTATCACAGAGGTATGGTCTTACAATGCCGAGCTCCTGGTTGCC ATGGAAAACCAACATACCATTGACTTGGCCGACAGCGAAATGGATAAACTATACGAGCGG GTCAAACGACAGCTGCGCGAGAATGCCGAGGAGGATGGAACTGGCTGCTTCGAAATCTTC CACAAGTGTGACGACGATTGTATGGCCAGCATCCGGAACAATACATATGATCATTCAAAA TATCGCGAGGAGGCTATGCAGAATAGAATTCAGATTGACCCCGTGAAGCTGAGCAGCGGG TACAAGGACGTCATTCTGTGGTTCAGTTTCGGAGCCTCTTGTTTTATCCTCCTCGCGATC GTGATGGGATTAGTGTTTATTTGTGTGAAGAACGGCAATATGAGGTGTACGATTTGTATC 599 ATGAACACGCAGATCTTGGTGTTCGCACTAATCGCGATAATCCCCACTAATGCAGACAAA ATTTGTTTAGGCCATCATGCTGTATCCAATGGCACAAAAGTCAACACCCTGACGGAAAGA GGTGTGGAAGTCGTCAACGCTACCGAGACTGTGGAACGGACGAATATCCCAAGGATCTGT TCAAAGGGGAAGCGAACGGTCGACCTGGGACAGTGCGGCCTGCTGGGGACCATCACAGGA CCGCCACAGTGCGACCAGTTTCTGGAGTTTTCTGCGGACTTGATTATCGAAAGACGGGAG GGAAGTGACGTATGCTATCCCGGCAAATTCGTGAATGAAGAGGCCTTGCGCCAGATATTA CGCGAGTCCGGAGGGATCGACAAGGAAGCTATGGGGTTCACATACTCCGGCATCAGAACC AACGGCGCCACATCCGCATGCCGGCGCAGTGGATCCAGCTTCTACGCAGAAATGAAATGG CTCCTCAGCAATACGGATAACGCCGCCTTCCCACAAATGACCAAGTCATACAAAAATACC AGAAAGAGCCCAGCCTTGATAGTGTGGGGAATCCACCACTCTGTGTCTACCGCCGAACAG ACTAAGCTGTATGGATCTGGCTCGAAATTAGTCACCGTCGGCTCCTCCAACTATCAGCAA TCATTCGTGCCAAGCCCCGGAGCCCGCCCACAGGTTAATGGACTGTCAGGAAGGATTGAC TTCCACTGGCTGATGCTGAATCCTAATGATACTGTGACTTTCTCATTTAATGGCGCTTTT ATTGCCCCTGACAGAGCCAGCTTCCTTCGAGGGAAGTCCATGGGAATCCAGTCTGGCGTG CAAGTAGACGCAAACTGTGAAGGGGATTGCTATCATAGTGGTGGGACAATCATTTCAAAT CTGCCCTTCCAGAATATCGATAGTAGAGCAGTAGGAAAATGTCCCAGGTACGTGAAACAG AGATCACTGTTATTGGCTACAGGAATGAAAAATGTCCCAGAAATCCCGAAGGGGAGAGGC CTCTTTGGGGCCATAGCAGGCTTTATTGAGAATGGGTGGGAAGGCCTAATCGATGGATGG TACGGGTTCCGCCATCAGAATGCGCAGGGCGAGGGGACTGCAGCCGACTACAAAAGCACG CAATCCGCTATCGACCAGATTACTGGAAAGCTCAACCGATTAATTGAAAAGACTAATCAG CAGTTCGAACTGATCGATAACGAGTTCAACGAGGTCGAAAAGCAGATCGGGAATGTGATC AACTGGACCAGGGATTCCATAACCGAGGTTTGGAGCTATAATGCAGAGTTGCTTGTAGCA ATGGAGAACCAACATACCATAGACCTGGCCGATTCGGAAATGGACAAGCTGTATGAGCGA GTGAAACGGCAGCTGCGGGAGAATGCAGAAGAAGACGGCACAGGTTGTTTTGAAATTTTT CACAAATGCGATGACGATTGCATGGCATCGATCAGAAATAACACCTATGATCATTCAAAG TATCGCGAGGAGGCCATGCAGAATAGGATCCAAATCGACCCTGTCAAACTCTCTAGTGGC TACAAGGATGTCATCCTCTGGTTCTCCTTTGGTGCCTCTTGCTTCATTTTGCTCGCCATT GTAATGGGATTGGTGTTCATTTGTGTTAAATCCAGAAATATGCGTTGTACCATTTGTATC 600 ATGAACACCCAGATTCTGGTCTTCGCTCTGATCGCCATTATACCAACAAATGCGGATAAA ATTTGCCTGGGACACCATGCTGTAAGCAACGGCACGAAGGTGAACACACTCACCGAAAGG GGAGTCGAAGTAGTCAATGCCACAGAGACCGTTGAACGTACGAACATCCCTAGAATTTGT AGCAAAGGGAAACGGACTGTCGATTTGGGACAATGTGGACTGCTTGGGACTATCACAGGG CCCCCTCAGTGCGATCAGTTCCTGGAATTCTCGGCCGATCTGATCATTGAACGGAGAGAA GGAAGCGACGTGTGCTACCCAGGTAAATTCGTGAACGAAGAGGCACTGCGCCAAATTCTT CGGGAGTCCGGCGGGATCGACAAGGAGGCAATGGGATTTACGTATTCTGGCATTAGGACC AACGGGGCTACATCTGCCTGCCGGCGAAGTGGATCCTCCTTCTATGCAGAAATGAAGTGG CTCCTTTCAAACACAGACAATGCCGCCTTTCCACAGATGACCAAGAGTTATAAGAATACC AGGAAAAGTCCTGCCTTGATTGTGTGGGGGATTCACCACTCCGTGAGCACTGCCGAGCAG ACCAAGCTTTACGGGAGCGGCAATAAGCTGGTGACAGTGGGCTCTTCCAATTATCAACAA TCCTTCGTGCCTAGCCCTGGGGAAAGACCCCAGGTGAATGGACTGTCCGGCCGGATCGAC TTTCACTGGCTCATGCTGAATCCCAACGACACTGTAACCTTTAGCTTTAACGGCGCCTTC ATCGCTCCCGATAGGGCGTCTTTCCTACGGGGGAAAAGTATGGGAATTCAATCAGGCGTC CAGGTAGACGCCAACTGCGAGGGTGACTGTTACCACAGCGGAGGTACAATAATTTCCAAC CTGCCTTTCCAAAACATAGATTCCCGCGCAGTGGGGAAATGCCCCAGGTACGTGAAGCAG CGAAGTCTCCTCCTTGCCACAGGAATGAAGAACGTGCCTGAGATTCCAAAAGGGCGGGGG TTGTTCGGGGCCATCGCTGGATTTATCGAAAACGGGTGGGAAGGCCTTATCGACGGCTGG TACGGTTTTAGGCACCAGAACGCACAGGGTGAGGGGACTGCGGCCGACTACAAGTCGACA CAAAGCGCTATAGACCAGATCACCGGGAAACTTAATCGGCTGATCGAAAAGACTAACCAG CAGTTTGAATTAATCGACAACGAATTTAATGAGGTGGAGAAGCAGATCGGAAACGTGATT AATTGGACCAGGGATTCCATCACGGAAGTTTGGTCCTATAACGCGGAGTTGCTTGTTGCC ATGGAAAACCAGCACACCATTGACCTCGCTGACTCTGAGATGGACAAACTATATGAGAGA GTCAAAAGACAGCTGCGCGAAAATGCAGAGGAGGATGGCACGGGTTGTTTCGAAATCTTT CACAAATGTGATGACGATTGTATGGCCAGTATACGGAATAACACCTATGACCACTCAAAG TACCGAGAAGAAGCCATGCAGAATCGCATCCAGATCGATCCTGTTAAGCTGTCCTCAGGA TATAAAGACGTCATCCTGTGGTTCTCTTTTGGCGCAAGCTGCTTTATCCTTTTAGCGATC GTGATGGGCCTGGTTTTTATATGTGTCAAGAATGGAAATATGCGGTGTACAATTTGCATC 601 ATGAACACTCAGATCTTAGTGTTTGCACTGATTGCCATAATCCCAACAAACGCCGATAAA ATCTGCCTGGGCCATCACGCGGTGTCGAATGGCACAAAGGTCAACACACTGACCGAAAGA GGCGTAGAGGTCGTGAACGCGACGGAGACCGTGGAGCGCACTAACATTCCTCGCATCTGT TCAAAAGGTAAGAAAACAGTGGATTTGGGACAGTGTGGCCTTCTCGGTACCATTACCGGC CCTCCCCAGTGCGACCAGTTCCTCGAATTTTCTGCTGATTTAATTATTGAACGGCGGGAG GGGTCAGACGTGTGTTATCCCGGCAAGTTTGTGAACGAAGAAGCTCTTAGACAGATCCTC CGGGAGAGCGGGGGGATTGACAAGGAAGCAATGGGCTTTACATACTCAGGTATTCGAACA AATGGAGCCACTAGCGCCTGCCGACGATCCGGGTCATCTTTCTACGCAGAGATGAAATGG CTGCTCAGCAACACTGATAATGCTGCCTTTCCACAGATGACAAAATCCTATAAAAACACC AGAAAATCCCCTGCGTTAATTGTCTGGGGCATCCACCATTCGGTTTCTACAGCAGAGCAG ACCAAGCTGTACGGCAGCGGAAATAAACTCGTGACTGTAGGATCGAGTAATTATCAGCAA AGCTTTGTTCCATCACCAGGGGCCCGTCCACAGGTCAATGGACAGAGTGGAAGGATCGAT TTCCATTGGCTAATGCTGAACCCAAACGATACTGTGACCTTTTCTTTCAACGGGGCCTTC ATTGCTCCTGATCGGGCATCATTTTTGCGTGGGAAGTCAATGGGTATACAATCAGGGGTG CAAGTGGACGCTAATTGCGAAGGTGACTGTTACCATTCTGGAGGCACCATTATCTCTAAC TTGCCTTTCCAAAACATTGACAGCAGAGCCGTGGGTAAGTGCCCTCGATACGTGAAGCAG CGGTCGCTTCTCCTTGCCACGGGCATGAAGAACGTGCCTGAAATCCCTAAAGGTCGTGGT CTATTCGGAGCAATTGCCGGTTTCATCGAGAATGGGTGGGAAGGCCTTATCGATGGTTGG TACGGGTTTCGGCACCAGAATGCCCAGGGCGAGGGCACAGCTGCTGACTACAAGTCGACC CAGAGCGCTATCGACCAGATCACAGGCAAGCTCAACAGGCTGATCGAAAAGACTAACCAG CAATTCGAATTGATCGATAACGAGTTTAATGAGGTGGAAAAGCAGATTGGGAATGTTATC AACTGGACCCGCGATTCCATTACTGAGGTATGGTCCTACAACGCTGAGCTCTTAGTCGCT ATGGAGAACCAGCACACCATAGATCTGGCTGATTCAGAGATGGATAAGCTCTATGAACGG GTTAAAAGGCAGCTTCGGGAGAACGCCGAGGAAGACGGAACTGGTTGCTTCGAGATCTTT CACAAATGTGACGATGACTGCATGGCTTCCATTAGAAATAACACGTATGACCATAGCAAG TATAGAGAGGAAGCAATGCAAAACCGGATCCAGATCGACCCAGTCAAATTGAGCTCGGGA TACAAGGACGTTATCCTGTGGTTCTCATTTGGCGCCTCCTGTTTCATATTGTTGGCTATT GTGATGGGTCTGGTGTTCATCTGTGTCAAGAATGGGAACATGAGGTGCACCATTTGTATA 602 ATGAACACACAGATTCTCGTGTTTGCGCTAATTGCAATCATACCCACTAATGCAGACAAA ATCTGTCTGGGACACCACGCGGTTAGCAATGGCACGAAGGTGAATACCCTGACAGAGAGA GGAGTGGAGGTTGTTAACGCGACCGAAACTGTTGAAAGGACTAATATCCCTCGTATCTGT TCAAAGGGAAAAAAGACCGTAGACCTGGGCCAGTGTGGACTGCTCGGCACGATCACAGGG CCACCTCAGTGTGACCAATTTCTGGAGTTCAGTGCTGACCTGATTATCGAAAGAAGAGAG GGATCAGACGTATGTTATCCCGGAAAGTTCGTGAATGAGGAAGCCCTTCGACAGATCTTA AGAGAATCAGGCGGGATCGATAAGGAAGCAATGGGCTTCACCTACTCTGGCATTCGGACC AATGGCGCAACTTCTGCATGCCGCAGATCCGGCTCTAGTTTTTACGCGGAGATGAAGTGG CTCCTCTCCAATACAGACAATGCAGCATTCCCACAAATGACCAAGTCTTATAAAAACACC CGCAAGTCCCCCGCTCTCATCGTTTGGGGTATCCACCATAGTGTGTCCACAGCCGAGCAA ACAAAGCTATACGGAAGTGGCAACAAGCTGGTCACAGTGGGCAGTAGTAATTATCAGCAG AGCTTCGTGCCTAGCCCCGGGGCCAGGCCACAGGTTAACGGCCAGTCAGGGCGCATCGAC TTTCACTGGCTTATGCTGAACCCGAACGACACTGTCACATTCTCATTCAACGGCGCCTTC ATAGCACCCGATAGGGCCTCATTTTTAAGGGGGAAGTCTATGGGAATTCAGTCCGGAGTG CAGGTCGACGCCAACTGTGAGGGCGACTGCTACCATAGTGGAGGAACCATCATAAGTAAT CTGCCATTTCAAAACATCGATTCACGCGCGGTGGGAAAATGCCCCAGGTATGTCAAGCAG CGGAGCCTTTTGCTTGCTACCGGGATGAAGAATGTGCCCGAGATTCCCAAGGGGAGAGGT TTATTCGGGGCTATAGCCGGGTTTATTGAAAACGGTTGGGAGGGGCTAATAGACGGATGG TACGGCTTCAGGCACCAGAATGCTCAAGGGGAAGGGACTGCCGCTGATTATAAGAGCACG CAGTCAGCTATCGACCAGATCACTGGGAAATTGAATCGTTTAATCGAGAAAACCAATCAG CAGTTCGAACTGATTGATAACGAGTTCAACGAGGTCGAGAAACAAATAGGAAACGTTATA AACTGGACACGAGATTCCATAACCGAGGTGTGGTCCTATAATGCTGAACTACTCGTAGCC ATGGAGAACCAGCATACCATTGATCTGGCCGACTCTGAGATGGACAAGCTATATGAACGG GTGAAAAGACAGTTGCGCGAAAACGCGGAAGAAGACGGGACAGGTTGCTTTGAAATTTTT CACAAATGCGATGACGACTGCATGGCTAGTATACGGAACAACACATACGATCACTCTAAG TATCGCGAGGAGGCAATGCAGAATCGCATCCAGATCGATCCCGTCAAACTGTCTTCCGGA TATAAAGATGTCATACTGTGGTTCTCTTTCGGCGCAAGCTGTTTCATTCTCCTAGCCATC GTCATGGGTCTGGTTTTCATATGTGTGAAGAACGGGAACATGCGGTGCACCATATGTATA 603 ATGAATACGCAGATCCTGGTGTTTGCTTTAATAGCCATCATCCCTACTAACGCAGACAAA ATTTGTCTCGGGCACCACGCCGTGTCTAATGGAACAAAGGTCAACACTCTGACAGAACGC GGAGTTGAAGTAGTGAATGCCACTGAAACTGTGGAGAGGACCAATATCCCTCGCATTTGT TCTAAGGGAAAGAAGACCGTCGACCTCGGTCAGTGCGGCCTATTGGGAACCATCACTGGC CCTCCTCAGTGTGACCAGTTTCTGGAGTTTAGTGCCGATTTGATCATCGAAAGAAGAGAG GGAAGCGACGTTTGTTATCCCGGAAAGTTTGTCAACGAGGAGGCTCTCCGCCAAATTCTC AGGGAATCTGGAGGTATCGACAAGGAAGCAATGGGCTTCACTTATTCAGGCATTCGCACA AACGGGGCCACCTCTGCATGCCGCCGCAGCGGCTCTAGCTTTTACGCCGAAATGAAATGG CTGCTCTCCAATACTGACAACGCTGCCTTTCCCCAAATGACCAAGTCCTATAAAAACACG CGCAAAAGTCCGGCCCTCATTGTGTGGGGGATTCACCACTCCGTCTCCACAGCCGAGCAG ACTAAGCTGTACGGTAGTGGTAATAAGTTGGTCACCGTGGGGTCAAGTAATTATCAGCAA AGCTTCGTCCCTAGCCCCGGGGCCAGACCCCAGGTGAACGGACAAAGCGGAAGGATCGAT TTTCACTGGCTGATGCTTAACCCTAATGACACCGTTACATTCAGTTTTAATGGTGCGTTT ATCGCCCCCGATCGGGCCTCCTTTCTTAGAGGCAAAAGTATGGGTATCCAGAGTGGAGTA CAGGTCGATGCCAATTGCGAAGGCGACTGCTATCACTCTGGGGGAACAATTATCTCCAAT TTACCGTTCCAGAACATCGACTCTAGGGCAGTCGGCAAATGCCCTAGATATGTAAAGCAG AGGTCTCTGCTGCTCGCCACGGGAATGAAAAACGTCCCAGAGATCCCAAAAGGCAGAGGA CTGTTCGGAGCCATAGCTGGCTTTATCGAGAACGGCTGGGAGGGACTGATCGATGGATGG TATGGTTTCCGGCACCAGAATGCACAAGGTGAGGGAACTGCCGCAGATTATAAGTCCACC CAAAGTGCCATCGATCAGATTACAGGCAAGTTAAACAGACTTATTGAAAAAACAAATCAA CAGTTTGAGCTTATTGACAACGAGTTCAATGAAGTTGAGAAGCAAATCGGTAACGTTATC AATTGGACTCGCGACTCCATCACCGAGGTGTGGTCTTACAACGCGGAACTACTTGTAGCG ATGGAAAATCAGCATACCATCGACTTGGCCGACTCGGAGATGGATAAGTTGTACGAGAGA GTGAAACGGCAGCTCAGGGAAAACGCGGAGGAGGACGGAACAGGTTGTTTCGAAATATTT CACAAGTGCGATGATGACTGTATGGCTAGCATTCGGAACAACACTTACGATCACTCCAAG TACCGTGAAGAGGCTATGCAGAACAGGATTCAGATCGATCCGGTGAAACTCTCAAGCGGA TACAAGGACGTTATACTTTGGTTCAGCTTCGGAGCTTCTTGCTTTATTCTTTTGGCTATC GTTATGGGACTAGTGTTTATATGTGTGAAAAACGGCAACATGCGCTGTACGATATGCATA 604 ATGAACACACAGATCCTTGTGTTTGCACTGATTGCCATCATTCCCACCAATGCCGACAAA ATCTGCTTAGGTCACCACGCTGTTAGCAACGGAACGAAGGTCAACACCCTGACCGAACGA GGCGTCGAAGTAGTTAATGCTACCGAAACTGTGGAGAGGACCAACATACCCAGGATCTGC AGTAAGGGTAAGAAGACAGTCGATCTAGGCCAGTGCGGACTACTCGGCACAATTACCGGA CCTCCCCAGTGCGACCAGTTTCTTGAGTTCAGTGCTGATCTTATTATAGAACGACGAGAA GGGAGTGATGTGTGCTATCCCGGCAAGTTTGTGAACGAAGAGGCGCTGCGACAAATCTTG AGGGAGTCAGGCGGGATTGACAAGGAAGCAATGGGGTTTACATATTCAGGTATTCGTACT AATGGAGCAACATCTGCCTGCCGGCGCAGTGGCTCCAGCTTTTACGCGGAAATGAAATGG CTGTTAAGTAACACCGACAATGCAGCATTTCCCCAAATGACAAAGAGTTATAAGAATACA CGAAAGTCACCCGCACTGATTGTATGGGGCATCCACCATTCGGTGTCGACCGCTGAACAG ACAAAATTGTACGGCTCAGGCAACAAACTGGTGACTGTTGGTTCTTCTAACTACCAGCAG AGCTTTGTCCCGTCACCCGGAGCCCGACCACAGGTGAATGGACAGTCCGGACGGATTGAC TTTCACTGGCTTATGCTCAATCCCAATGATACTGTGACATTTAGTTTCAACGGGGCCTTT ATAGCTCCCGATCGGGCTTCTTTTCTTCGAGGAAAATCAATGGGCATTCAATCCGGAGTT CAGGTGGACGCCAATTGTGAAGGAGACTGTTACCATTCCGGAGGTACAATTATTTCCAAC CTGCCTTTCCAAAATATCGATAGTCGAGCCGTGGGAAAGTGTCCCAGATATGTAAAACAG AGAAGTCTATTGCTGGCTACAGGGATGAAAAATGTGCCCGAAATACCCAAGGGACGGGGA TTGTTTGGTGCCATAGCTGGGTTTATCGAGAATGGGTGGGAAGGCCTTATCGACGGCTGG TATGGCTTTCGGCACCAAAACGCGCAGGGTGAGGGGACCGCGGCAGACTACAAGTCTACT CAGAGCGCAATTGATCAGATTACCGGCAAACTGAACCGACTAATAGAAAAAACAAACCAG CAGTTTGAGCTCATTGATAATGAATTCAACGAAGTGGAGAAGCAGATTGGGAACGTGATC AATTGGACGCGCGATTCCATCACTGAGGTGTGGAGTTACAATGCCGAACTCCTGGTGGCC ATGGAAAACCAGCACACAATTGACCTCGCTGACTCTGAGATGGACAAGTTGTATGAGCGC GTGAAGCGGCAGCTTAGAGAGAACGCCGAGGAAGACGGGACAGGGTGTTTTGAGATCTTC CATAAGTGCGATGACGACTGCATGGCATCCATCCGTAACAACACATATGATCACTCAAAG TATAGGGAGGAAGCCATGCAGAACAGGATTCAGATCGACCCTGTGAAACTCTCATCAGGG TACAAAGATGTAATCTTGTGGTTTTCGTTTGGAGCTTCGTGCTTCATTCTGCTAGCGATT GTCATGGGCCTTGTGTTTATCTGCGTCAAGAACGGCAACATGAGGTGTACTATCTGTATA 605 ATGAATACCCAGATTCTGGTGTTTGCGCTGATTGCCATAATCCCCACTAACGCTGATAAG ATCTGCCTGGGGCACCATGCAGTGTCTAATGGCACTAAGGTCAATACGCTCACGGAGAGA GGCGTGGAAGTGGTTAATGCTACCGAAACTGTGGAACGGACTAACATTCCAAGAATCTGT TCAAAGGGTAAGAAAACTGTGGACCTCGGCCAATGTGGCTTGCTGGGCACCATCACTGGG CCACCACAGTGTGATCAGTTTCTCGAGTTCTCTGCCGATTTAATCATCGAGCGCCGGGAA GGATCAGATGTGTGCTACCCGGGTAAATTCGTGAATGAGGAAGCACTGAGACAGATTCTG CGTGAATCAGGAGGGATTGATAAGGAGGCTATGGGGTTTACATACTCTGGCATCAGAACA AATGGGGCCACCAGCGCGTGCCGGCGCTCTGGGAGTTCTTTCTACGCTGAAATGAAATGG CTGCTTTCTAACACGGACAATGCCGCTTTCCCCCAGATGACAAAAAGCTACAAGAACACT CGCAAGAGCCCTGCACTCATAGTGTGGGGCATCCACCACTCCGTCTCTACTGCAGAGCAG ACCAAGCTGTACGGCAGCGGGAACAAGCTTGTAACCGTTGGATCTTCAAACTACCAACAA TCATTCGTTCCCTCTCCTGGAGCCCGGCCCCAAGTTAATGGGCAGTCCGGGAGAATCGAC TTCCATTGGCTGATGCTAAATCCCAATGATACAGTTACCTTTAGCTTTAACGGCGCCTTC ATCGCTCCGGATAGAGCGAGCTTCCTTCGCGGTAAGTCTATGGGAATCCAGTCCGGGGTG CAAGTCGACGCAAACTGCGAGGGAGACTGTTACCATTCCGGGGGTACTATCATTTCAAAT TTACCCTTTCAGAACATTGATAGCCGCGCCGTAGGCAAATGTCCTAGGTATGTGAAACAG AGAAGCCTGCTCCTGGCAACCGGAATGAAGAACGTGCCTGAGATCCCTAAGGGTAGAGGA CTTTTCGGAGCTATCGCCGGGTTCATCGAGAACGGTTGGGAGGGACTCATTGATGGGTGG TATGGTTTCCGCCACCAGAACGCCCAAGGGGAAGGCACTGCTGCTGACTATAAATCAACG CAGTCCGCCATAGACCAGATTACAGGTAAATTAAATAGACTGATTGAGAAAACAAACCAG CAATTCGAGCTAATCGACAATGAGTTTAATGAGGTCGAGAAGCAGATCGGTAACGTCATA AATTGGACACGGGATAGTATCACCGAAGTGTGGAGCTACAATGCTGAGCTCCTAGTTGCC ATGGAGAATCAACATACGATCGACCTGGCGGATTCTGAAATGGACAAGTTATACGAAAGA GTGAAGCGACAGCTAAGAGAGAATGCAGAGGAAGACGGCACTGGCTGCTTCGAAATATTT CACAAGTGTGATGATGACTGTATGGCAAGCATCAGGAATAACACCTACGACCACAGTAAG TATAGAGAGGAGGCAATGCAGAACAGGATACAGATCGATCCCGTCAAACTTTCCAGTGGC TATAAGGACGTTATCCTTTGGTTCTCGTTTGGGGCGAGCTGCTTCATCTTGCTGGCGATC GTGATGGGCCTCGTGTTTATTTGCGTGAAAAACGGAAACATGAGGTGTACAATTTGTATT 606 ATGAATACACAAATTCTGGTCTTCGCACTGATCGCCATAATCCCCACTAACGCAGACAAG ATCTGTCTCGGTCACCACGCCGTTTCGAATGGTACTAAGGTAAATACGCTGACAGAGAGG GGGGTGGAAGTCGTGAACGCCACTGAGACCGTCGAAAGGACAAACATTCCCCGCATCTGT TCGAAGGGAAAGAAGACCGTCGATCTTGGGCAGTGCGGTCTCTTGGGTACGATCACAGGG CCTCCTCAGTGCGATCAATTCCTGGAGTTTTCAGCCGACCTGATAATCGAAAGAAGGGAG GGAAGCGATGTGTGTTACCCCGGGAAGTTCGTGAATGAGGAAGCCCTGCGACAGATCCTA AGGGAGAGCGGGGGAATCGATAAAGAGGCAATGGGGTTCACCTATAGTGGAATCAGAACT AACGGCGCCACTTCCGCCTGCCGGAGATCGGGTAGCTCTTTCTATGCTGAAATGAAATGG CTGCTCAGTAATACAGACAACGCGGCGTTCCCACAGATGACCAAGTCCTATAAGAATACC CGGAAATCTCCTGCGCTTATTGTGTGGGGCATCCACCACTCTGTGTCCACCGCTGAGCAG ACAAAACTTTACGGATCAGGAAATAAGCTCGTCACCGTGGGAAGCTCCAATTATCAGCAA TCCTTCGTGCCATCCCCCGGAGCAAGACCACAGGTGAATGGACAGTCCGGGAGGATCGAT TTCCACTGGTTGATGCTGAACCCCAATGATACTGTCACGTTCAGCTTCAACGGTGCTTTT ATTGCTCCCGATAGGGCCAGCTTTCTGAGAGGCAAGTCCATGGGCATCCAGAGCGGGGTC CAAGTGGACGCTAATTGCGAGGGTGATTGCTACCACTCTGGAGGCACCATCATCAGCAAC CTGCCTTTCCAGAATATAGATTCCCGGGCGGTGGGGAAGTGCCCAAGATACGTCAAGCAA CGGAGCCTCCTCCTTGCGACTGGAATGAAAAACGTGCCAGAGATTCCAAAGGGGAGGGGC CTGTTTGGAGCGATTGCCGGATTCATCGAGAATGGCTGGGAAGGGCTCATTGACGGATGG TATGGCTTTCGCCATCAGAACGCCCAGGGAGAGGGGACCGCGGCCGACTACAAGTCCACC CAAAGCGCCATTGACCAAATCACAGGAAAGCTGAATCGCCTAATCGAAAAGACTAATCAG CAGTTCGAGCTGATAGATAATGAGTTCAACGAGGTCGAGAAACAAATCGGAAATGTCATC AATTGGACCCGCGACTCTATAACAGAAGTTTGGTCCTATAACGCGGAGCTGCTAGTCGCC ATGGAAAACCAGCACACTATTGACCTTGCCGATAGCGAAATGGACAAGCTGTATGAAAGG GTGAAAAGACAGCTGCGCGAGAATGCAGAAGAGGACGGTACCGGCTGTTTCGAGATTTTC CATAAGTGTGACGACGACTGCATGGCATCGATTCGAAACAACACATACGACCACTCTAAG TATAGAGAGGAGGCCATGCAGAACAGAATCCAGATCGATCCTGTGAAGCTGTCATCCGGG TACAAGGATGTCATTCTTTGGTTCTCATTCGGTGCGTCTTGTTTCATCCTGCTCGCCATA GTCATGGGGCTGGTCTTCATTTGCGTGAAAAACGGGAACATGCGGTGTACAATTTGCATC 607 ATGAATACCCAGATACTCGTGTTTGCCCTTATCGCTATAATCCCCACGAATGCAGACAAA ATCTGCCTTGGGCATCACGCCGTGAGTAATGGCACCAAAGTGAACACATTGACCGAGCGG GGGGTGGAGGTAGTCAATGCCACCGAAACAGTGGAACGCACCAACATTCCTCGGATCTGT AGCAAAGGAAAGAAAACAGTCGATCTGGGCCAGTGTGGCCTGTTAGGAACCATCACTGGA CCGCCTCAATGCGATCAGTTTCTCGAATTCAGCGCGGATCTCATTATTGAAAGAAGAGAG GGTTCTGACGTGTGTTACCCCGGCAAGTTTGTGAACGAAGAAGCACTCCGCCAGATACTT AGGGAGTCCGGCGGGATCGACAAAGAGGCTATGGGGTTTACTTATAGTGGAATCCGCACG AACGGGGCCACGTCCGCCTGCAGACGGAGCGGCTCCTCATTTTACGCGGAGATGAAGTGG CTGCTCAGCAACACAGACAATGCCGCCTTTCCCCAGATGACAAAGTCTTACAAGAACACC AGAAAGTCGCCAGCCCTCATAGTCTGGGGGATACATCACAGCGTTTCCACCGCCGAGCAG ACTAAGCTGTATGGCAGCGGAAATAAACTGGTGACTGTGGGCTCCAGCAATTACCAGCAA AGCTTTGTACCCAGCCCCGGAGCAAGGCCCCAAGTGAATGGCCAGTCTGGTAGAATCGAT TTCCATTGGCTTATGTTGAACCCTAACGACACGGTTACATTCAGTTTCAATGGGGCATTT ATCGCCCCCGACCGTGCCTCTTTCTTGAGGGGTAAATCTATGGGCATCCAGTCAGGTGTG CAGGTGGATGCTAATTGCGAAGGCGACTGCTATCACAGTGGCGGTACTATCATATCCAAT CTGCCTTTTCAAAACATCGATTCCCGTGCGGTGGGGAAGTGTCCTCGATACGTGAAACAG CGCTCATTGCTGTTGGCCACCGGAATGAAAAACGTGCCAGAGATCCCAAAGGGCAGAGGT CTGTTCGGAGCTATTGCTGGCTTTATCGAAAACGGCTGGGAAGGGCTGATTGACGGCTGG TATGGATTTAGGCACCAAAATGCTCAAGGCGAGGGCACAGCCGCCGACTATAAAAGCACT CAAAGTGCGATAGACCAGATCACAGGCAAGCTGAACCGCCTGATTGAGAAAACAAACCAG CAGTTCGAACTCATTGACAACGAATTCAACGAAGTGGAGAAACAGATCGGAAATGTTATC AATTGGACAAGAGACAGTATTACAGAGGTGTGGTCCTATAACGCCGAGCTCCTGGTCGCT ATGGAGAATCAGCATACCATCGACCTGGCGGATTCAGAGATGGACAAACTTTATGAGAGA GTTAAAAGACAACTGCGTGAGAATGCTGAAGAAGATGGAACTGGATGCTTCGAAATTTTT CATAAGTGTGATGATGACTGTATGGCGTCAATCCGGAATAACACCTACGATCACTCCAAA TATAGAGAAGAGGCAATGCAGAATCGTATTCAGATAGACCCTGTGAAATTGTCCAGTGGA TACAAGGACGTAATTTTGTGGTTCAGCTTCGGGGCTTCCTGTTTCATCCTCCTCGCCATC GTGATGGGTCTCGTTTTCATATGCGTGAAGAACGGGAATATGAGGTGCACGATATGTATC 608 ATGAACACCCAGATTCTGGTGTTCGCTCTCATCGCAATCATACCCACCAATGCTGACAAA ATCTGTTTGGGGCATCATGCCGTCAGCAACGGCACTAAGGTCAATACTCTTACAGAACGC GGGGTTGAGGTTGTCAATGCAACTGAAACCGTGGAAAGAACGAATATCCCACGTATTTGC AGTAAGGGCAAGAAAACCGTGGACCTCGGGCAATGCGGGCTGCTTGGAACGATTACCGGC CCACCCCAATGCGATCAGTTCCTCGAGTTTTCTGCAGATTTGATTATTGAGCGAAGGGAG GGCTCCGACGTCTGTTATCCTGGAAAGTTTGTGAATGAGGAGGCACTGCGCCAGATACTC CGTGAAAGCGGCGGGATTGATAAGGAGGCCATGGGCTTTACTTACTCGGGAATACGCACA AATGGAGCCACTAGCGCCTGCCGGAGGTCTGGATCAAGCTTCTACGCAGAAATGAAGTGG TTACTAAGCAACACAGATAACGCAGCTTTCCCACAGATGACAAAAAGCTATAAGAATACT CGCAAGTCCCCTGCCCTGATAGTATGGGGCATCCACCACTCTGTCTCTACCGCCGAACAG ACTAAGCTGTATGGAAGCGGGAATAAACTGGTTACAGTGGGAAGCAGTAACTATCAGCAG AGTTTTGTCCCATCCCCAGGCGCTAGGCCACAAGTCAACGGACAGAGCGGGAGAATAGAT TTTCATTGGCTCATGTTAAATCCTAACGACACAGTGACTTTCTCGTTTAATGGCGCTTTT ATCGCCCCTGATAGGGCCTCTTTTTTAAGAGGCAAGAGCATGGGAATCCAGTCTGGAGTG CAGGTCGATGCTAATTGCGAAGGCGACTGCTACCACAGCGGAGGAACAATCATCTCTAAT TTGCCCTTCCAGAATATTGATAGTCGCGCAGTGGGCAAATGCCCCCGGTACGTAAAGCAG CGCTCACTCCTGCTGGCAACAGGGATGAAAAATGTCCCTGAGATCCCAAAGGGCAGAGGA CTGTTTGGTGCCATTGCCGGATTCATCGAGAACGGATGGGAGGGGCTGATCGACGGATGG TATGGATTCCGGCATCAGAACGCCCAGGGCGAAGGGACAGCCGCTGATTATAAGTCCACC CAATCAGCCATTGATCAGATTACCGGCAAACTAAATCGCTTGATTGAGAAAACAAATCAG CAATTCGAATTGATTGACAATGAGTTTAATGAGGTTGAGAAACAGATCGGAAACGTGATT AATTGGACACGGGATTCTATAACCGAGGTCTGGTCATACAATGCTGAACTTCTGGTCGCG ATGGAGAACCAGCACACAATTGACCTGGCCGATAGTGAAATGGATAAGTTATACGAACGG GTCAAACGGCAGCTGAGGGAGAACGCCGAAGAAGACGGTACCGGTTGTTTCGAAATCTTC CATAAGTGTGATGACGACTGCATGGCCTCAATTCGGAACAACACCTACGATCACAGCAAG TATAGAGAAGAGGCTATGCAAAACCGCATACAGATCGACCCAGTAAAATTAAGTAGTGGC TACAAAGATGTGATTCTTTGGTTCTCCTTTGGAGCCAGCTGCTTTATTCTGCTGGCAATA GTTATGGGCCTCGTCTTTATCTGTGTCAAGAATGGAAACATGAGGTGTACTATTTGCATA 609 ATGAACACGCAGATCCTTGTATTTGCGCTCATAGCAATAATCCCTACGAATGCAGATAAG ATTTGCCTGGGACACCATGCTGTCTCTAACGGAACCAAGGTCAATACACTGACTGAACGT GGCGTTGAGGTGGTGAATGCAACTGAGACCGTTGAGCGAACCAACATCCCCCGCATTTGC TCTAAGGGAAAGAAGACAGTCGATCTCGGACAGTGTGGCCTGCTCGGCACAATTACGGGG CCCCCTCAGTGCGATCAGTTCTTGGAATTCTCTGCCGACCTCATCATCGAGCGCCGGGAA GGCTCTGACGTTTGTTATCCTGGCAAATTCGTGAACGAGGAGGCATTGAGGCAAATCTTG AGAGAATCTGGAGGTATAGATAAGGAAGCCATGGGCTTTACGTACTCTGGGATTAGGACC AATGGTGCAACTTCTGCGTGCCGTAGGAGCGGAAGTTCTTTCTACGCTGAGATGAAATGG CTGCTGTCGAATACTGATAATGCCGCTTTTCCCCAGATGACCAAGTCTTACAAGAATACC AGGAAGTCTCCTGCCCTGATTGTGTGGGGTATCCACCACAGCGTGTCCACAGCCGAACAA ACCAAACTTTATGGCTCAGGTAATAAGCTCGTCACTGTCGGTAGCTCTAATTATCAGCAG TCTTTTGTCCCTAGCCCCGGGGCTAGGCCACAGGTCAACGGCCAGAGCGGACGGATTGAC TTCCACTGGCTGATGCTGAACCCGAACGACACAGTAACGTTTAGCTTCAATGGCGCCTTT ATTGCCCCGGACCGAGCTTCATTCCTGCGGGGTAAGAGTATGGGGATCCAATCAGGTGTT CAGGTGGACGCCAATTGCGAAGGCGATTGCTATCATTCCGGGGGTACCATTATCTCCAAC CTCCCATTTCAAAATATTGATAGCAGGGCCGTGGGCAAATGTCCCAGGTATGTTAAGCAG CGTTCTCTGTTACTGGCCACTGGCATGAAGAATGTCCCTGAAATCCCAAAGGGCAGAGGA CTGTTCGGCGCGATCGCGGGATTTATCGAAAACGGATGGGAGGGCTTGATCGATGGCTGG TATGGGTTTCGACATCAGAACGCCCAAGGGGAGGGAACCGCCGCTGATTATAAAAGCACC CAGAGTGCCATTGATCAGATCACGGGCAAACTGAACCGGCTCATTGAGAAAACAAACCAG CAGTTCGAACTCATCGATAACGAGTTTAATGAGGTGGAGAAACAAATCGGCAACGTTATT AACTGGACTAGGGATTCTATCACGGAGGTCTGGTCCTACAACGCAGAACTGCTGGTGGCA ATGGAAAATCAACATACTATTGATCTGGCCGATTCCGAAATGGACAAGCTTTACGAGAGG GTCAAGAGACAGCTGAGAGAGAACGCTGAAGAGGATGGGACCGGATGCTTCGAAATCTTT CATAAGTGTGATGATGATTGCATGGCCAGTATCCGTAATAATACATATGATCATTCTAAA TACCGCGAAGAGGCGATGCAGAATCGAATCCAAATTGACCCAGTTAAACTGTCTAGTGGC TACAAAGACGTCATCCTGTGGTTTTCGTTCGGAGCTTCTTGCTTCATTCTGTTGGCAATA GTGATGGGCCTCGTATTTATATGTGTGAAAAACGGGAATATGAGATGCACAATTTGTATT 610 ATGAATACCCAGATCCTGGTGTTCGCCCTTATTGCCATCATTCCGACCAACGCTGACAAA ATCTGTCTCGGACACCACGCTGTCTCCAATGGGACAAAGGTGAATACCTTGACCGAGCGA GGGGTCGAGGTCGTCAACGCGACAGAAACAGTGGAGAGGACCAACATTCCCCGGATATGC TCAAAGGGCAAAAGAACGGTGGATCTGGGGCAATGCGGGCTGCTGGGCACTATAACCGGA CCCCCCCAATGTGACCAGTTTCTTGAATTTTCTGCCGATCTGATAATCGAACGCCGGGAA GGATCCGACGTGTGCTATCCTGGAAAGTTTGTGAATGAGGAAGCCCTCCGGCAGATTCTG AGGGAATCCGGAGGGATAGATAAGGAAGCAATGGGGTTCACTTATAGCGGTATCCGCACA AATGGGGCGACTAGTGCATGTCGTCGAAGTGGAAGCAGTTTCTATGCCGAGATGAAATGG CTGCTAAGCAATACAGACAACGCCGCATTCCCACAGATGACCAAGTCCTATAAAAATACA AGAAAGAGTCCCGCGCTTATCGTGTGGGGCATACATCACTCCGTCAGCACCGCCGAACAG ACCAAGCTCTATGGCTCAGGCAACAAGTTGGTGACAGTCGGCAGTAGCAATTACCAGCAG TCCTTCGTGCCTAGCCCAGGCGAAAGGCCTCAGGTGAATGGTTTGAGCGGCCGAATAGAC TTCCATTGGTTAATGCTCAATCCTAACGATACAGTCACGTTCAGTTTCAATGGTGCCTTT ATAGCGCCTGATCGCGCATCATTCCTGCGTGGAAAATCTATGGGCATTCAGAGCGGAGTC CAGGTCGACGCCAACTGCGAAGGCGACTGTTATCACTCCGGGGGCACCATTATTTCCAAT TTGCCCTTCCAGAACATTGATAGCAGAGCAGTTGGCAAGTGCCCGCGCTACGTAAAACAA AGGTCTCTGCTTTTGGCTACAGGTATGAAAAATGTCCCAGAAATTCCCAAGGGCCGCGGA TTGTTCGGGGCGATCGCTGGTTTTATTGAGAACGGTTGGGAAGGCCTCATCGATGGGTGG TATGGTTTTCGGCATCAGAACGCCCAGGGCGAAGGCACTGCCGCGGATTATAAGTCCACC CAGTCAGCGATCGATCAGATCACAGGAAAGCTGAACCGACTTATCGAAAAAACAAACCAG CAGTTTGAACTAATTGACAATGAATTCAACGAGGTGGAGAAACAGATTGGCAATGTGATT AACTGGACCCGTGATAGCATCACAGAGGTCTGGAGCTATAATGCAGAACTGTTGGTTGCT ATGGAGAATCAGCACACCATCGACCTGGCCGACTCTGAAATGGACAAACTGTACGAGCGA GTGAAACGGCAGCTGCGTGAGAACGCTGAGGAAGACGGCACCGGTTGTTTCGAAATCTTC CATAAATGCGACGACGACTGTATGGCTTCTATTAGAAACAATACCTACGATCACTCCAAG TACCGGGAGGAAGCAATGCAGAATCGAATCCAGATCGACCCAGTTAAGTTGTCCAGCGGA TACAAGGACGTGATTCTATGGTTTAGTTTTGGAGCCTCCTGCTTCATTCTTCTGGCCATT GTGATGGGTTTGGTTTTTATCTGTGTAAAAAATGGAAATATGCGCTGTACTATTTGTATT 611 ATGAACACTCAGATTCTTGTGTTCGCTCTGATCGCAATTATACCCACAAACGCGGATAAA ATCTGCCTTGGACATCACGCAGTGTCGAACGGAACTAAGGTGAACACTCTCACCGAGCGG GGCGTCGAAGTAGTCAATGCTACAGAGACCGTCGAACGCACTAATATTCCACGTATCTGC TCCAAGGGGAAAAGGACCGTCGACCTGGGACAATGTGGCTTGCTAGGGACTATTACCGGC CCACCGCAGTGTGATCAATTCCTCGAGTTCTCAGCCGACCTGATCATCGAGCGACGCGAG GGCAGCGATGTCTGTTACCCCGGGAAATTTGTTAATGAGGAAGCATTAAGGCAGATCCTG CGCGAGTCTGGCGGGATCGACAAGGAGGCCATGGGCTTTACATATTCCGGGATCCGGACA AACGGCGCCACAAGTGCCTGTCGACGGTCAGGATCATCATTCTATGCCGAGATGAAATGG CTTCTCAGCAATACCGATAACGCTGCATTTCCACAGATGACAAAGTCGTATAAAAACACA AGAAAGTCACCCGCTCTGATTGTTTGGGGAATTCACCACAGTGTCTCAACCGCAGAACAG ACCAAGTTGTACGGGAGTGGAAACAAGTTGGTAACCGTGGGATCTTCAAACTATCAGCAG AGCTTCGTGCCAAGCCCCGGGGAACGCCCCCAAGTGAATGGACTGTCTGGACGGATTGAC TTCCACTGGCTGATGCTGAACCCCAACGACACAGTGACATTCAGTTTTAATGGAGCATTT ATCGCCCCGGACAGAGCAAGCTTTCTCAGGGGTAAGAGTATGGGAATTCAGAGTGGTGTA CAGGTTGACGCTAACTGCGAAGGTGACTGTTATCATTCTGGTGGGACTATCATCTCCAAC CTGCCTTTCCAGAACATTGACTCCAGAGCAGTCGGCAAGTGCCCCAGGTACGTGAAGCAA AGGTCTTTGCTGCTCGCAACCGGCATGAAGAACGTGCCTGAAATACCTAAGGGCCGTGGC TTGTTTGGCGCAATCGCGGGATTTATCGAAAATGGGTGGGAGGGGTTGATTGACGGTTGG TACGGCTTCCGTCATCAGAATGCCCAAGGGGAGGGCACCGCCGCAGACTATAAAAGCACC CAAAGTGCAATCGATCAGATCACCGGCAAATTGAACCGGCTGATTGAGAAAACGAATCAG CAGTTCGAACTGATCGACAACGAATTTAACGAGGTCGAAAAGCAGATTGGAAATGTGATC AACTGGACCCGGGATTCCATCACCGAAGTCTGGTCATATAACGCGGAACTGCTTGTAGCA ATGGAGAATCAACACACTATCGATCTGGCGGACAGTGAGATGGATAAGCTCTACGAGAGG GTTAAGAGACAACTGCGCGAGAATGCTGAGGAAGATGGTACCGGGTGTTTCGAGATTTTT CACAAATGTGATGATGACTGCATGGCTAGTATTCGCAACAACACATATGATCACTCCAAA TACCGCGAAGAGGCTATGCAGAACCGCATCCAAATAGATCCCGTAAAGCTTAGCTCGGGT TACAAAGATGTAATCTTATGGTTTAGTTTCGGAGCGAGCTGTTTTATTCTACTCGCCATT GTGATGGGGCTTGTCTTCATATGTGTGAAGAATGGAAATATGCGCTGCACAATCTGTATA 612 ATGAATACCCAGATTCTTGTCTTCGCACTCATAGCTATTATTCCTACGAACGCGGACAAG ATTTGTCTGGGGCATCACGCCGTCTCCAATGGGACAAAAGTGAACACCCTGACTGAACGA GGGGTTGAAGTGGTCAATGCAACTGAAACAGTGGAACGGACAAACATTCCAAGAATCTGT TCCAAAGGAAAGCGAACAGTGGACCTGGGACAGTGCGGCCTGCTGGGTACCATTACTGGC CCCCCACAGTGCGACCAGTTCCTGGAATTTAGCGCAGATCTTATCATCGAGCGGCGGGAA GGAAGTGACGTGTGTTATCCCGGGAAGTTTGTAAACGAGGAGGCCCTCCGGCAGATCCTT CGTGAGAGCGGCGGGATTGATAAAGAGGCTATGGGCTTTACCTATTCCGGAATAAGAACC AACGGGGCCACTTCTGCGTGTCGTAGGAGCGGCAGCAGCTTCTACGCCGAAATGAAGTGG CTGTTGTCTAACACCGATAATGCCGCCTTCCCTCAGATGACCAAGTCCTATAAGAACACC CGGAAATCCCCTGCCCTGATTGTTTGGGGGATTCACCATTCCGTATCTACCGCCGAACAG ACCAAGTTGTACGGTTCCGGAAACAAGCTCGTCACAGTTGGCTCCTCCAATTACCAGCAG AGTTTCGTACCTTCTCCCGGCGCAAGACCACAGGTCAACGGACTAAGCGGGCGGATTGAC TTTCACTGGCTCATGTTGAATCCAAATGACACTGTAACCTTTAGTTTCAACGGTGCCTTT ATAGCACCAGATCGGGCCAGCTTTCTGCGTGGAAAGTCTATGGGCATTCAAAGTGGTGTG CAAGTGGATGCTAACTGTGAGGGAGATTGCTACCATTCAGGTGGGACAATCATTAGCAAT CTTCCGTTTCAGAATATTGATTCACGGGCTGTGGGCAAGTGCCCCCGTTACGTGAAGCAG AGAAGCCTGCTTCTTGCCACGGGAATGAAGAATGTTCCCGAAATACCAAAGGGTAGGGGT CTCTTCGGAGCAATAGCCGGATTTATCGAGAATGGCTGGGAGGGGCTTATCGATGGTTGG TACGGCTTTCGCCATCAGAACGCTCAGGGAGAGGGGACCGCAGCAGACTACAAATCCACC CAGTCTGCTATCGACCAGATCACTGGCAAGCTGAATCGGATAATCGAGAAGACTAACCAG CAGTTTGAGCTGATCGACAATGAGTTTAACGAAGTGGAGAAACAGATTGGCAATGTGATC AATTGGACAAGAGATTCCATTACGGAAGTTTGGTCATATAATGCCGAGCTCCTGGTTGCA ATGGAGAACCAACATACAATCGACCTGGCGGACAGTGAGATGGACAAGCTGTACGAGCGT GTGAAGCGCCAACTCCGGGAAAATGCTGAGGAAGACGGCACGGGCTGCTTTGAAATCTTC CACAAGTGTGACGACGACTGCATGGCAAGCATAAGGAACAACACCTATGATCATTCTAAG TACAGAGAGGAGGCGATGCAGAATCGCATCCAGATTGACCCAGTTAAGCTTTCCAGCGGG TACAAAGACGTCATCTTGTGGTTTTCCTTTGGTGCCTCTTGTTTCATTTTGCTCGCTATC GTAATGGGACTGGTATTCATCTGCGTGAAAAATGGAAATATGAGATGCACCATCTGCATT 613 ATGAACACACAAATTCTGGTGTTCGCTCTCATCGCAATAATTCCTACCAACGCCGATAAG ATTTGCCTGGGGCACCATGCGGTCAGTAACGGAACCAAAGTCAATACACTCACAGAAAGA GGCGTTGAGGTGGTGAATGCCACAGAAACTGTTGAACGTACAAATATTCCGCGAATCTGT TCTAAAGGCAAGAAAACCGTTGATCTGGGTCAATGCGGCCTTCTGGGAACCATTACAGGG CCACCTCAGTGCGACCAGTTTCTCGAATTTTCTGCTGATCTCATTATCGAGAGGCGGGAA GGCAGTGACGTTTGCTACCCTGGTAAGTTCGTAAATGAGGAGGCCCTCAGGCAGATCCTG AGGAAGTCCGGCGGTATTGATAAGGAAGCCATGGGCTTCACTTATTCTGGGATCAGGACC AACGGGGCCACTTCAACATGTAGAAGGTCCGGAAGCTCTTTCTATGCAGAGATGAAATGG CTCCTGAGCAACACAGACAACGCCGCCTTTCCACAGATGACCAAGAGCTATAAGAATACT CGCAAATCTCCAGCCATCATAGTGTGGGGTATCCACCACAGCGTGTCCACGGCCGAGCAG ACAAAGCTGTATGGGAGCGGCAACAAGCTGGTGACTGTCGGTAGCTCGAATTACCAGCAG TCTTTCGTGCCTAGCCCCGGGGCCCGGCCGCAGGTCAATGGGCTTTCCGGGCGAATCGAC TTTCACTGGTTGATGTTAAACCCAAACGACACGGTGACATTCAGCTTTAACGGCGCCTTT ATTGCACCTGACCGCGCATGTTTCCTGAGGGGCAAGTCTATGGGTATCCAGTCTGGTGTA CAAGTCGACGCCGACTGTGAAGGAGACTGCTACCATTCCGGCGGGACAATAATCTCAAAC CTACCCTTCCAGAACATCGACAGTAGGGCGGTGGGCAAGTGTCCTAGGTACGTGAAACAG CGGAGCCTGCTGTTGGCCACAGGCATGAAGAATGTCCCCGAAATTCCAAAGGGGCGGGGT CTCTTTGGAGCAATTGCAGGATTCATTGAGAATGGTTGGGAAGGTCTCATCGATGGATGG TACGGGTTCCGCCATCAGAACGCCCAGGGTGAGGGGACCGCAGCCGACTATAAGAGTACC CAGTCAGCGATCGACCAAATCACCGGCAAGCTAAATCGGCTGATTGAGAAGACAAACCAA CAGTTTGAATTAATTGACAACGAGTTTAATGAGGTGGAAAGACAGATCGGCAACGTGATC AACTGGACACGCGATTCCATCACAGAAGTCTGGTCTTATAATGCAGAGCTGCTAGTGGCC ATGGAGAATCAGCACACCATTGATCTAGCCGACTCTGAAATGGACAAGTTGTATGAACGG GTAAAACGTCAGTTACGAGAAAATGCCGAGGAAGATGGCACAGGGTGTTTCGAGATTTTT CACAAATGTGACGACGATTGTATGGCAAGTATTCGTAACAACACATACGACCACAGCAAA TACAGAGAGGAGGCCATGCAGAACCGCATCCAGATAGACCCAGTTAAACTGAGCTCCGGG TACAAGGATGTGATCCTCTGGTTTAGTTTCGGCGCAAGTTGTTTCATCCTACTCGCGATA GTTATGGGCCTGGTATTCATTTGCGTCAAGAACGGGAACATGAGGTGTACCATCTGCATT 614 ATGAATACCCAGATTCTCGTGTTTGCTTTGATTGCTATCATCCCCACGAATGCTGATAAA ATTTGCCTAGGCCATCATGCTGTGTCTAACGGGACCAAGGTGAACACCCTCACTGAGAGA GGCGTGGAGGTCGTGAACGCGACCGAGACTGTTGAGCGCACAAACATTCCCAGGATTTGT AGCAAAGGAAAAAGAACCGTTGATCTCGGCCAATGCGGCCTCCTGGGTACCATCACGGGG CCTCCACAGTGTGACCAGTTCTTGGAATTCAGTGCAGACCTTATCATCGAGCGCAGGGAG GGCTCTGATGTATGCTACCCTGGAAAATTCGTGAACGAGGAGGCTTTGAGACAAATCCTG AGGGAGTCTGGAGGCATCGATAAGGAGGCCATGGGCTTTACATACAGCGGCATTCGCACT AACGGAGCCACTTCCGCATGCAGGCGGTCCGGCAGCTCATTCTACGCTGAAATGAAGTGG CTCCTGAGTAATACGGATAACGCCGCCTTTCCGCAGATGACCAAAAGTTATAAGAATACA AGGAAATCACCTGCTCTCATTGTCTGGGGTATCCACCACTCGGTGAGCACCGCTGAGCAG ACCAAACTGTACGGGTCAGGCAATAAACTTGTGACCGTGGGCTCAAGCAATTACCAGCAG TCCTTTGTGCCTTCACCCGGCGAAAGACCTCAAGTCAACGGACTGTCTGGTCGGATCGAC TTTCACTGGCTGATGTTAAACCCAAATGATACAGTGACATTCTCCTTCAACGGAGCATTC ATAGCCCCCGATAGGGCCAGCTTCCTCCGGGGGAAATCCATGGGAATTCAGTCAGGCGTC CAGGTTGACGCTAACTGCGAGGGTGACTGTTATCATTCCGGAGGTACTATAATAAGCAAT CTTCCATTCCAGAATATAGATTCACGAGCGGTCGGCAAGTGTCCGCGGTACGTTAAACAG CGTAGCTTACTGCTCGCAACCGGGATGAAAAACGTTCCAGAAATTCCTAAGGGCAGAGGG CTGTTTGGGGCCATCGCCGGCTTCATCGAGAACGGTTGGGAAGGGCTCATCGATGGCTGG TACGGTTTTAGACACCAGAATGCCCAGGGCGAGGGGACCGCAGCAGATTACAAGAGCACA CAGTCAGCCATAGATCAAATTACTGGGAAGCTCAATCGGTTGATAGAAAAGACTAACCAG CAGTTCGAATTGATCGATAATGAATTTAACGAGGTCGAGAAACAAATCGGCAATGTTATT AATTGGACTAGAGACTCCATCACAGAAGTGTGGTCCTACAATGCCGAACTGCTGGTGGCT ATGGAGAACCAGCACACAATCGACCTTGCAGACAGTGAGATGGATAAACTGTATGAGAGA GTGAAAAGGCAGCTCCGCGAGAACGCTGAGGAAGATGGAACCGGCTGTTTTGAAATTTTC CATAAGTGCGACGATGATTGCATGGCTTCTATCCGGAATAATACTTACGACCACAGTAAG TACCGAGAAGAAGCCATGCAGAATCGAATTCAGATAGACCCCGTCAAGCTGAGCTCCGGC TATAAAGATGTGATTCTGTGGTTCAGCTTTGGGGCCTCTTGTTTCATTCTTTTGGCCATC GTGATGGGCCTTGTGTTCATTTGTGTAAAAAATGGCAATATGAGGTGCACAATATGTATT 615 ATGAATACCCAGATACTGGTGTTCGCCCTGATTGCAATCATCCCAACTAACGCTGATAAG ATTTGTCTCGGTCACCACGCTGTGAGTAACGGAACTAAAGTTAACACACTGACAGAGAGG GGAGTGGAGGTTGTTAACGCGACAGAGACAGTGGAGCGCACTAATATACCACGGATATGT AGTAAGGGAAAAAGAACTGTGGACTTGGGTCAATGCGGACTGTTGGGGACGATAACTGGC CCCCCTCAGTGTGATCAGTTTCTGGAGTTCTCAGCCGATCTGATCATCGAGAGGCGAGAG GGGAGTGATGTGTGTTATCCTGGTAAGTTTGTGAATGAGGAGGCTCTCAGGCAAATCCTC AGGGAATCTGGAGGGATCGATAAGGAGGCTATGGGCTTCACTTACTCTGGAATAAGAACT AACGGCGCCACTAGCGCCTGTAGGCGATCCGGAAGTTCGTTCTACGCTGAAATGAAGTGG TTGCTCAGCAACACTGACAACGCAGCATTTCCCCAAATGACCAAAAGCTATAAGAATACT CGCAAGTCTCCCGCCCTGATAGTGTGGGGGATTCACCATAGTGTCTCTACAGCCGAGCAG ACTAAATTATACGGCAGTGGCAACAAGCTGGTGACGGTGGGGAGTTCAAATTACCAGCAG AGCTTCGTGCCCAGTCCGGGAGCTCGCCCTCAAGTTAATGGTCTTTCCGGCAGAATTGAT TTTCACTGGCTGATGCTTAACCCTAACGACACCGTGACCTTTTCCTTCAACGGCGCTTTC ATTGCCCCGGACCGAGCTAGTTTCCTTAGGGGGAAGTCTATGGGCATACAGTCTGGTGTG CAAGTTGATGCGAATTGCGAGGGGGATTGTTACCACTCTGGAGGTACAATCATCAGTAAT TTACCCTTCCAGAACATTGATAGTAGAGCCGTTGGGAAGTGTCCACGGTATGTTAAACAG CGCAGCCTGCTTCTGGCCACAGGGATGAAGAATGTCCCCGAAATCCCCAAAGGCAGAGGA TTGTTCGGCGCAATCGCGGGGTTTATTGAAAACGGTTGGGAAGGCCTCATTGACGGCTGG TACGGGTTCCGGCACCAGAATGCTCAAGGAGAGGGCACCGCCGCCGATTATAAGTCTACC CAGAGCGCCATCGACCAGATCACAGGCAAATTGAACCGAATTATCGAGAAGACCAACCAA CAGTTCGAGCTTATCGACAACGAATTTAATGAAGTAGAAAAGCAGATCGGAAACGTTATT AACTGGACTCGGGACAGTATTACTGAAGTGTGGTCCTATAATGCTGAGCTGTTGGTGGCA ATGGAGAACCAGCACACCATTGACCTGGCCGACAGCGAGATGGACAAGCTTTACGAAAGA GTGAAGCGACAGCTTCGGGAAAACGCCGAGGAAGATGGAACCGGCTGTTTTGAAATCTTC CATAAGTGCGATGATGACTGTATGGCCAGTATACGCAACAACACTTATGACCATTCAAAA TACCGCGAAGAAGCCATGCAGAATCGGATCCAGATCGACCCTGTGAAGCTGTCGAGCGGG TATAAGGACGTGATACTGTGGTTCAGCTTCGGAGCCAGCTGCTTCATTCTGCTGGCTATT GTCATGGGCCTGGTGTTCATTTGCGTCAAAAATGGTAATATGAGGTGTACGATCTGCATC 616 ATGAACACTCAGATCCTCGTGTTTGCCTTGATCGCAATAATCCCCACCAATGCCGATAAG ATATGTCTCGGACACCACGCTGTGTCCAACGGGACCAAGGTTAATACTCTGACAGAGCGG GGCGTTGAAGTGGTGAATGCCACCGAAACCGTGGAACGGACAAATATTCCACGAATTTGC AGCAAGGGAAAGAAGACCGTGGACCTTGGTCAGTGTGGGCTGCTGGGGACTATCACCGGG CCTCCCCAATGCGACCAGTTCCTCGAGTTCTCTGCAGATCTGATTATTGAGCGGCGCGAG GGTAGTGATGTGTGCTACCCTGGCAAATTCGTGAATGAGGAGGCACTGAGACAGATCCTG AGAGAGAGTGGCGGAATCGATAAAGAAGCAATGGGGTTTACCTATTCCGGGATACGGACT AACGGGGCAACATCGGCTTGCAGGCGAAGTGGCTCATCTTTCTACGCCGAAATGAAGTGG CTCCTGAGCAACACCGATAATGCCGCTTTCCCACAGATGACTAAGTCCTATAAGAACACC CGGAAGAGCCCGGCCTTGATTGTCTGGGGGATCCACCATTCTGTCAGTACAGCTGAACAA ACTAAGTTGTACGGTTCCGGAAACAAGCTGGTGACCGTGGGATCTAGCAATTATCAGCAG TCATTCGTGCCTTCACCTGGCGCACGACCACAGGTCAATGGACAGAGTGGTAGAATCGAC TTTCACTGGCTGATGCTTAATCCGAATGACACCGTGACCTTCTCCTTCAACGGAGCCTTT ATTGCCCCTGACCGAGCTAGCTTTCTCAGGGGAAAGTCTATGGGCATACAGAGCGGCGTG CAGGTCGACGCAAATTGTGAAGGGGACTGTTACCACTCAGGCGGGACCATTATAAGTAAT CTGCCTTTTCAGAACATTGACAGCAGAGCGGTGGGCAAATGTCCGCGTTACGTGAAGCAG AGATCACTGCTCTTGGCCACCGGCATGAAGAATGTCCCTGAGATCCCGAAAGGCAGGGGT CTGTTTGGGGCTATTGCGGGCTTCATTGAAAACGGCTGGGAAGGTCTCATCGATGGTTGG TACGGATTCCGGCACCAGAATGCTCAGGGGGAGGGCACCGCCGCCGATTATAAGAGTACC CAGTCTGCCATCGACCAAATCACCGGCAAGCTTAACCGTCTTATCGAGAAAACAAATCAG CAGTTCGAGCTGATCGATAACGAATTTAATGAGGTAGAGAAACAGATTGGTAATGTGATT AACTGGACACGCGACTCCATTACCGAGGTGTGGTCGTATAATGCAGAATTACTGGTGGCC ATGGAGAATCAACACACCATTGATCTGGCCGATAGCGAGATGGACAAGCTGTATGAGAGA GTGAAGAGACAACTGAGGGAAAACGCGGAGGAGGATGGAACAGGATGTTTCGAGATCTTC CACAAGTGTGACGACGATTGCATGGCGAGTATCCGGAACAACACCTACGATCATTCAAAA TATCGAGAGGAAGCTATGCAAAACCGAATTCAGATCGATCCAGTAAAATTATCTTCAGGG TATAAGGATGTCATACTATGGTTCAGCTTCGGGGCGTCGTGCTTCATCTTGCTGGCTATC GTCATGGGGCTCGTCTTTATTTGTGTGAAAAATGGAAATATGCGGTGCACGATCTGCATT 617 ATGAACACGCAAATCCTGGTATTTGCGCTGATCGCTATCATTCCCACTAATGCTGACAAA ATCTGTCTGGGCCATCACGCTGTGTCAAACGGAACCAAGGTGAATACGCTGACCGAACGC GGCGTCGAGGTGGTCAATGCCACGGAAACAGTCGAAAGAACAAACATTCCCAGAATCTGC TCAAAGGGTAAAAAGACGGTAGATCTCGGGCAGTGTGGGCTTCTTGGAACAATCACTGGC CCACCACAATGCGATCAATTTCTCGAATTCAGCGCCGACCTGATCATCGAGAGGAGGGAA GGTAGTGATGTGTGCTACCCCGGGAAGTTTGTGAATGAGGAGGCATTGCGCCAAATACTG AGAGAGAGCGGAGGGATTGACAAGGAGGCCATGGGATTCACCTACAGCGGGATCAGAACT AATGGAGCCACGAGCGCTTGCAGGAGGAGTGGAAGCAGCTTTTATGCTGAAATGAAGTGG CTACTGTCCAATACGGATAACGCTGCGTTCCCACAAATGACAAAGTCGTACAAGAATACG CGAAAGAGCCCAGCCCTCATTGTCTGGGGTATCCATCACAGCGTGAGTACCGCAGAACAA ACCAAACTTTACGGGTCAGGTAACAAACTGGTAACCGTTGGAAGCTCCAATTATCAGCAA TCGTTCGTTCCTTCACCTGGGGCTCGCCCACAAGTCAATGGACAGAGCGGCAGAATTGAC TTCCATTGGCTCATGCTCAATCCAAACGATACAGTCACCTTTTCATTTAACGGAGCTTTC ATCGCTCCTGATCGGGCTAGCTTTCTAAGGGGCAAGTCTATGGGTATTCAGTCCGGCGTA CAAGTCGACGCCAACTGTGAGGGGGACTGCTACCATAGCGGAGGCACTATCATATCAAAT CTCCCCTTCCAGAATATCGACTCCAGGGCTGTTGGTAAGTGCCCAAGATACGTGAAGCAG AGATCCCTCCTTCTGGCTACAGGCATGAAAAATGTGCCAGAAATTCCAAAGGGACGGGGC CTATTTGGAGCTATTGCAGGCTTCATCGAGAACGGATGGGAAGGACTGATCGATGGGTGG TACGGATTTAGGCACCAGAACGCCCAGGGAGAGGGAACAGCTGCTGACTACAAATCTACC CAGTCTGCAATTGATCAGATCACCGGTAAACTGAATAGACTGATTGAGAAAACTAACCAG CAGTTCGAGCTAATTGATAATGAGTTCAATGAAGTGGAGAAGCAGATCGGCAACGTGATT AACTGGACCAGAGATTCAATCACGGAGGTCTGGTCTTACAACGCCGAGTTGCTGGTGGCT ATGGAAAACCAGCACACCATAGACCTGGCCGACTCTGAAATGGACAAATTGTACGAGAGG GTAAAAAGGCAGCTCCGAGAAAACGCCGAGGAGGACGGTACTGGCTGCTTTGAGATATTT CACAAGTGCGACGATGATTGCATGGCCTCCATTCGAAACAACACGTACGACCACAGTAAA TACAGGGAGGAAGCCATGCAGAACCGCATCCAGATTGACCCTGTCAAGCTGAGTAGTGGC TACAAGGACGTTATCCTCTGGTTTAGTTTTGGAGCATCATGTTTTATACTGTTGGCAATA GTCATGGGGCTTGTCTTCATCTGCGTGAAAAATGGCAACATGCGTTGTACAATCTGCATT 618 ATGAATACCCAAATTCTGGTGTTCGCTCTAATTGCCATCATACCAACAAACGCAGACAAG ATTTGTCTGGGCCACCACGCCGTGTCAAACGGAACGAAAGTGAACACTCTGACTGAGCGT GGCGTGGAGGTAGTGAACGCTACCGAAACTGTGGAGCGGACTAATATCCCAAGGATCTGT AGCAAGGGAAAAAAGACAGTGGACCTGGGTCAGTGCGGATTGCTAGGAACCATAACCGGT CCACCTCAGTGCGATCAGTTTTTGGAGTTTAGCGCCGATCTCATCATCGAAAGAAGGGAG GGTTCTGATGTTTGTTACCCAGGAAAATTTGTTAACGAAGAAGCCCTTCGCCAGATCCTT AGAGAATCAGGCGGCATCGATAAAGAGGCAATGGGGTTCACCTATTCAGGAATACGCACA AATGGCGCCACGAGCGCGTGCAGGCGCAGCGGGAGTTCATTTTATGCTGAAATGAAATGG CTCCTCTCAAACACTGATAACGCTGCATTTCCACAAATGACGAAAAGTTATAAGAATACG AGAAAGTCTCCAGCCCTCATTGTCTGGGGCATTCATCACTCAGTGTCGACTGCCGAGCAA ACCAAGCTGTACGGCAGCGGTAACAAATTGGTAACTGTCGGCAGTAGTAACTACCAGCAA AGTTTTGTGCCTAGCCCCGGCGCTCGGCCACAAGTGAACGGACAGAGCGGGCGCATCGAT TTTCACTGGCTGATGCTAAATCCAAATGACACAGTCACCTTTTCGTTTAACGGGGCCTTC ATCGCCCCTGACCGGGCTTCTTTCCTGAGAGGAAAAAGCATGGGAATCCAGTCCGGAGTC CAGGTTGACGCCAACTGCGAAGGAGACTGTTATCATTCCGGGGGCACTATTATAAGCAAT CTGCCTTTTCAGAACATAGATAGTCGCGCCGTAGGCAAGTGTCCCCGCTACGTCAAACAG AGAAGCCTTCTGCTGGCTACCGGTATGAAGAACGTCCCCGAAATCCCTAAAGGCCGAGGA CTATTCGGCGCTATCGCCGGCTTCATTGAAAATGGCTGGGAGGGCTTGATAGATGGGTGG TATGGCTTTCGCCATCAGAATGCACAGGGTGAAGGGACTGCAGCCGATTATAAATCTACT CAGTCCGCCATCGATCAGATTACCGGGAAGCTCAATAGACTCATTGAGAAGACAAATCAA CAGTTCGAACTGATCGATAACGAGTTCAACGAGGTAGAGAAACAGATCGGGAATGTCATT AACTGGACCCGAGATTCTATCACAGAAGTTTGGTCTTACAACGCGGAGCTGCTGGTCGCA ATGGAAAATCAGCATACCATCGATCTGGCCGATTCAGAAATGGACAAGCTTTATGAGAGA GTGAAGCGCCAGTTGCGCGAGAATGCGGAAGAGGACGGCACCGGATGCTTCGAGATTTTT CACAAATGTGATGATGATTGTATGGCTTCGATTCGGAATAACACCTACGATCACTCCAAA TATCGCGAAGAGGCTATGCAGAACAGAATACAAATCGATCCCGTCAAACTTAGCAGCGGC TACAAAGACGTCATTCTGTGGTTTTCCTTCGGGGCATCCTGTTTTATACTGCTGGCCATA GTGATGGGTCTGGTGTTTATATGTGTAAAGAACGGCAACATGCGCTGTACCATTTGCATC 619 ATGAACACCCAGATCCTCGTGTTCGCCTTAATCGCTATCATTCCAACCAATGCAGACAAG ATATGTCTGGGTCATCATGCCGTTAGCAATGGCACCAAGGTCAACACCCTGACCGAGCGC GGAGTCGAGGTTGTTAATGCAACCGAAACTGTGGAGCGGACAAATATTCCCCGGATCTGC AGCAAGGGGAAGAGGACAGTCGATCTGGGCCAATGCGGACTGCTGGGCACAATCACCGGA CCCCCTCAGTGCGATCAATTTCTGGAGTTCAGCGCCGACCTGATCATCGAGAGAAGGGAG GGGAGTGACGTATGTTACCCAGGGAAGTTTGTGAACGAGGAGGCCCTGAGACAGATTCTG AGAGAAAGCGGCGGCATCGATAAAGAGGCCATGGGATTTACCTATAGCGGCATTCGCACC AATGGAGCCACTTCAGCTTGTAGGAGATCCGGGAGTAGCTTTTACGCTGAGATGAAATGG CTGCTTTCCAATACTGATAATGCCGCTTTCCCACAGATGACTAAGTCTTATAAGAATACT CGCAAGAGTCCTGCCCTGATAGTCTGGGGCATCCATCATTCCGTCTCAACCGCTGAACAG ACCAAACTCTACGGGTCTGGGAACAAGTTGGTGACCGTGGGCTCCTCGAATTATCAACAA TCATTCGTGCCGTCCCCCGGCGCTCGGCCGCAGGTTAACGGTCTTTCAGGCCGCATCGAC TTCCACTGGCTAATGTTGAACCCAAACGATACTGTTACTTTTAGCTTTAACGGCGCATTT ATTGCCCCCGACCGGGCCTCCTTCCTGCGAGGCAAGTCCATGGGTATCCAGTCTGGAGTC CAAGTGGATGCTAACTGTGAAGGCGACTGTTACCATAGTGGAGGGACAATTATTAGTAAC CTGCCCTTCCAGAACATTGACAGTAGGGCCGTGGGCAAATGCCCACGGTACGTGAAGCAG CGGTCCCTGCTGCTGGCAACTGGAATGAAGAACGTGCCAGAGATCCCTAAAGGGCGGGGC CTCTTCGGCGCTATCGCCGGGTTTATAGAGAATGGTTGGGAAGGGCTGATCGATGGATGG TATGGGTTCCGCCACCAGAATGCTCAGGGTGAGGGGACAGCTGCTGACTACAAGTCTACA CAGAGTGCTATTGACCAGATCACCGGAAAACTTAACAGGATCATCGAGAAAACGAATCAG CAATTTGAGCTCATTGATAACGAGTTCAATGAAGTCGAGAAGCAAATCGGGAACGTGATA AATTGGACACGCGACTCCATCACTGAGGTCTGGAGCTATAACGCCGAGCTTCTGGTGGCA ATGGAGAATCAGCATACTATCGATCTCGCGGATTCCGAAATGGATAAGCTCTACGAGAGA GTTAAGAGGCAGCTCCGCGAGAATGCCGAGGAAGATGGGACCGGATGCTTCGAGATATTC CATAAGTGCGACGACGACTGCATGGCGTCAATAAGGAATAATACTTATGATCATTCTAAG TACAGGGAGGAGGCCATGCAGAATCGCATTCAGATTGATCCTGTTAAACTAAGCTCAGGC TATAAGGACGTAATATTATGGTTTTCTTTTGGCGCTTCCTGTTTTATCCTCCTGGCTATA GTTATGGGGCTGGTGTTTATTTGTGTTAAAAATGGAAATATGAGATGCACAATTTGCATC 620 ATGAATACCCAAATTCTGGTCTTCGCTCTGATAGCTATAATCCCAACGAATGCCGATAAG ATATGTCTGGGTCATCACGCTGTCTCCAATGGGACCAAAGTGAACACATTGACTGAACGC GGCGTGGAGGTGGTTAACGCCACTGAGACCGTAGAGCGGACTAATATACCCCGGATCTGC AGTAAGGGAAAAAAGACAGTCGACTTGGGTCAGTGCGGCCTGCTAGGGACCATCACAGGG CCTCCTCAATGTGACCAGTTCCTGGAGTTCAGCGCAGACCTTATAATCGAAAGAAGAGAG GGGTCGGACGTCTGTTACCCCGGCAAGTTTGTGAACGAGGAAGCACTGAGGCAGATCCTG AGAGAATCCGGCGGAATTGATAAGGAAGCCATGGGTTTCACCTACAGTGGCATACGCACC AATGGAGCAACATCCGCTTGTAGACGGAGCGGTTCTTCCTTTTACGCCGAGATGAAGTGG CTGCTGTCCAACACGGATAATGCAGCCTTCCCTCAAATGACTAAGAGTTATAAGAATACG AGAAAGTCCCCCGCCTTGATTGTGTGGGGGATCCACCATAGCGTTAGCACAGCCGAACAG ACTAAGCTTTACGGTTCAGGCAACAAGCTCGTAACCGTGGGATCCTCCAATTATCAGCAA TCCTTCGTGCCTTCTCCTGGCGCCCGCCCTCAGGTTAACGGTCAAAGCGGTCGCATAGAT TTTCATTGGCTCATGCTGAACCCGAATGATACAGTCACGTTTTCTTTCAATGGGGCATTT ATCGCACCAGACCGGGCCTCCTTTCTTCGCGGGAAGTCTATGGGAATACAATCCGGCGTA CAGGTTGATGCTAACTGCGAGGGCGACTGTTATCATTCAGGGGGTACCATAATCTCCAAC TTGCCTTTCCAAAATATTGATTCCCGGGCTGTCGGAAAGTGCCCGAGATATGTGAAGCAA CGCAGTTTACTCCTGGCCACGGGAATGAAAAACGTTCCCGAAATCCCTAAGGGAAGGGGA CTATTTGGTGCTATTGCAGGGTTTATTGAGAATGGCTGGGAGGGCTTAATCGACGGCTGG TATGGCTTCCGCCACCAAAACGCACAGGGGGAGGGGACAGCAGCAGACTATAAAAGCACG CAGAGCGCAATCGACCAAATTACCGGCAAGTTGAATAGGCTCATTGAAAAAACAAACCAG CAATTTGAGCTCATCGACAACGAGTTCAATGAAGTTGAGAAACAGATAGGAAATGTGATC AATTGGACTCGCGACAGCATTACCGAGGTATGGTCATACAACGCAGAGCTCTTAGTGGCG ATGGAGAACCAGCACACCATCGATCTAGCCGACAGTGAGATGGACAAGCTGTACGAACGA GTCAAGAGACAGTTACGAGAGAATGCCGAGGAGGACGGAACCGGCTGCTTTGAGATTTTC CACAAGTGTGACGATGACTGTATGGCTAGCATTCGCAATAATACCTATGACCACAGTAAA TACCGGGAGGAGGCTATGCAGAATCGTATTCAGATCGATCCTGTGAAGCTGTCTAGTGGA TACAAGGACGTAATCCTGTGGTTTTCTTTCGGTGCTTCTTGTTTCATCCTGTTAGCAATA GTAATGGGTCTGGTATTTATCTGCGTTAAGAACGGAAATATGCGGTGTACTATTTGCATC 621 ATGAACACACAGATACTGGTCTTTGCTCTTATCGCTATCATTCCCACCAATGCCGATAAA ATCTGCTTGGGGCACCACGCCGTGTCCAACGGGACGAAAGTTAATACACTCACTGAGCGA GGCGTGGAGGTCGTCAACGCCACAGAGACGGTGGAGCGCACCAACATCCCGAGGATCTGC AGCAAGGGCAAACGAACCGTCGATCTTGGGCAGTGCGGGCTGTTGGGCACCATTACGGGA CCTCCCCAGTGTGATCAGTTCTTGGAGTTTTCTGCTGACCTCATCATTGAGAGAAGGGAA GGCAGCGACGTGTGCTATCCCGGCAAGTTCGTGAAAGAAGAGGCCCTGCGGCAGATACTG CGGGAGTCAGGCGGTATTGATAAAGAAGCGATGGGCTTCACGTACAGCGGTATCAGGACT AACGGCGCTACCAGCGCTTGCCGACGGAGCGGTAGCTCTTTCTACGCCGAGATGAAATGG TTACTTTCTAACACCGATAACGCTGCGTTTCCACAGATGACGAAATCCTACAAGAATACT AGAAAAAGTCCAGCCCTGATCGTTTGGGGAATTCACCACTCTGTCTCCACAGCTGAACAG ACCAAGTTGTATGGCTCCGGCAACAAGCTGGTTACAGTAGGCTCCAGCAATTACCAGCAG TCTTTTGTCCCCTCCCCTGGAGCTCGTCCACAGGTCAATGGACTGTCAGGCCGAATCGAC TTCCACTGGCTGATGTTGAATCCAAACGATACAGTGACTTTCTCATTTAATGGCGCTTTT ATTGCCCCAGATCGGGCCAGTTTCCTCAGAGGTAAGTCCATGGGAATCCAGTCGGGGGTC CAAGTCGATGCCAACTGCGAAGGCGACTGTTACCACAGCGGCGGTACCATTATCTCCAAC CTGCCCTTCCAAAACATCGACTCTCGGGCAGTTGGAAAATGTCCAAGGTACGTCAAGCAG AGATCCCTGCTGCTGGCCACAGGCATGAAGAACGTGCCCGAGATTCCCAAAGGACGGGGC CTATTCGGAGCGATCGCAGGATTCATTGAGAACGGATGGGAGGGCTTGATTGATGGCTGG TACGGCTTTAGACACCAAAATGCTCAGGGGGAGGGCACTGCCGCCGACTACAAATCTACT CAGTCGGCGATTGACCAGATTACTGGAAAGTTGAACCGGCTCATTGAAAAAACCAACCAG CAGTTCGAATTGATTGATAATGAGTTCAATGAAGTGGAAAAACAGATCGGGAATGTGATT AACTGGACCAGAGACTCCATCACAGAGGTTTGGAGCTACAACGCGGAATTACTAGTTGCC ATGGAAAATCAGCACACCATTGACCTCGCTGACAGTGAGATGGATAAACTGTACGAGCGC GTGAAAAGACAGCTACGCGAGAATGCGGAAGAAGACGGCACAGGATGCTTTGAGATCTTT CACAAGTGCGACGATGATTGCATGGCTTCGATTCGGAATAATACCTACGATCACTCCAAA TATAGAGAGGAGGCTATGCAAAATCGAATTCAGATCGACCCCGTCAAGTTGTCCTCCGGC TACAAGGACGTTATCTTGTGGTTCTCCTTTGGCGCATCATGCTTCATTTTGCTGGCCATA GTCATGGGCCTGGTATTCATTTGTGTCAAGAATGGAAATATGAGGTGCACCATATGCATC 622 ATGAATACCCAGATTCTTGTGTTCGCTCTGATCGCGATTATTCCTACCAACGCTGATAAA ATCTGCCTCGGACATCACGCTGTTAGCAACGGAACCAAGGTGAACACACTGACAGAGCGC GGGGTCGAAGTTGTCAACGCTACTGAGACGGTGGAACGGACCAACATACCACGGATCTGC TCTAAGGGCAAGCGAACTGTGGATCTCGGGCAGTGTGGCTTGCTGGGAACGATTACGGGC CCTCCTCAGTGTGATCAGTTTCTCGAGTTCTCTGCAGATCTGATAATCGAGAGAAGGGAA GGATCAGATGTCTGCTACCCTGGGAAATTCGTGAAAGAAGAAGCACTGAGACAAATCTTA CGCGAGTCAGGGGGCATAGATAAGGAAGCCATGGGCTTCACATACTCTGGGATCCGTACC AACGGCGCCACGTCAGCTTGTCGTAGGTCTGGCTCTTCTTTCTATGCCGAGATGAAATGG CTCCTGTCGAATACTGACAATGCTGCGTTCCCCCAGATGACTAAGAGCTACAAAAATACA AGAAAGTCTCCCGCGCTGATAGTTTGGGGGATTCACCACTCTGTCTCCACTGCCGAACAG ACAAAGTTATACGGCAGCGGTAACAAGCTAGTGACAGTTGGGAGCTCAAACTATCAACAA TCATTTGTACCATCCCCCGGTGCCAGGCCACAGGTAAACGGCCTTTCCGGACGTATCGAC TTTCACTGGCTGATGCTGAATCCCAATGATACCGTAACTTTTTCCTTCAACGGGGCTTTT ATTGCCCCAGATAGGGCATCCTTTCTGCGAGGTAAGAGTATGGGCATACAGAGCGGCGTG CAAGTGGACGCTAATTGTGAGGGGGACTGCTACCATTCCGGGGGAACCATCATCTCGAAT TTACCGTTTCAGAACATCGATTCACGCGCTGTTGGGAAGTGTCCTAGGTATGTAAAACAG CGATCCCTTCTTCTGGCCACAGGCATGAAGAACGTACCAGAGATACCTAAAGGACGGGGA CTGTTCGGGGCCATTGCAGGGTTCATCGAAAACGGCTGGGAAGGCCTGATCGACGGCTGG TATGGCTTTCGGCATCAGAACGCCCAGGGAGAGGGTACTGCAGCCGATTATAAGAGTACA CAGTCTGCAATCGACCAAATTACAGGAAAGCTGAATAGACTCATAGAGAAGACAAATCAG CAGTTTGAACTCATTGACAATGAGTTCAATGAAGTGGAAAAGCAAATCGGGAACGTGATT AATTGGACCAGGGATAGCATAACAGAAGTCTGGTCCTATAACGCTGAACTACTTGTTGCA ATGGAGAACCAGCACACTATCGATCTGGCAGACTCTGAAATGGACAAACTGTATGAGAGG GTTAAACGCCAACTGAGAGAGAATGCTGAGGAAGACGGTACTGGCTGTTTTGAGATTTTC CACAAATGTGACGACGATTGTATGGCGTCCATCAGGAACAACACCTATGACCATTCTAAA TATAGAGAGGAAGCCATGCAGAATCGGATACAGATTGATCCTGTGAAACTTAGCTCTGGA TATAAGGACGTGATCCTGTGGTTTTCATTTGGAGCGTCATGCTTTATCCTGCTGGCCATC GTGATGGGATTGGTCTTCATATGTGTCAAGAATGGCAATATGCGGTGTACCATATGTATT 623 ATGAATACACAGATACTCGTGTTTGCCCTCATTGCCATCATCCCTACCAATGCAGATAAG ATCTGCCTCGGCCACCATGCTGTTAGCAACGGAACCAAGGTTAACACCCTCACTGAACGA GGAGTGGAGGTCGTTAACGCCACAGAAACCGTGGAACGGACGAACATCCCCCGCATCTGC AGCAAAGGCAAGCGCACCGTGGATCTGGGGCAGTGCGGCCTGCTGGGCACGATTACAGGG CCCCCCCAATGCGACCAGTTTTTGGAGTTCAGCGCAGACCTGATCATTGAAAGGCGTGAG GGGAGTGACGTGTGTTATCCCGGTAAATTTGTGAACGAAGAGGCCCTCAGACAGATCCTG CGGGAGTCTGGTGGGATCGATAAAGAGGCAATGGGCTTCACTTATTCTGGAATCCGGACC AACGGGGCCACCTCTGCGTGCAGGCGTTCCGGCAGCTCATTCTATGCAGAGATGAAATGG CTACTTAGTAACACGGACAACGCAGCTTTCCCCCAGATGACTAAAAGTTACAAGAACACT CGAAAGAGTCCAGCACTCATTGTGTGGGGGATTCATCATTCCGTGTCTACCGCCGAGCAG ACTAAACTATACGGTAGTGGGAATAAACTAGTAACCGTCGGCTCTTCTAACTACCAGCAG TCTTTTGTGCCCTCTCCAGGTGAACGCCCCCAGGTCAACGGGCTGTCTGGTCGCATCGAC TTTCATTGGCTGATGCTCAACCCTAATGACACAGTCACGTTCAGTTTCAATGGTGCTTTC ATTGCACCCGATAGGGCCTCATTTCTTCGGGGCAAGTCCATGGGCATCCAAAGTGGAGTT CAGGTGGACGCCAATTGCGAAGGTGACTGCTATCACAGTGGCGGCACAATCATTTCTAAC CTGCCGTTTCAGAATATTGACTCCCGTGCTGTAGGGAAGTGTCCCCGATACGTGAAGCAG CGGTCCTTGCTTCTGGCAACCGGTATGAAGAATGTCCCTGAGATTCCTAAAGGCCGGGGG CTGTTCGGAGCTATTGCAGGGTTCATCGAAAACGGCTGGGAGGGGCTCATCGATGGTTGG TACGGATTCAGACATCAAAATGCACAAGGGGAAGGAACCGCAGCCGACTATAAGAGCACA CAAAGCGCTATCGATCAGATCACCGGGAAATTAAACCGCCTGATTGAGAAAACCAATCAG CAGTTCGAGCTTATTGACAACGAATTCAATGAGGTGGAAAAACAGATAGGGAATGTGATC AACTGGACCAGAGATTCTATCACCGAGGTTTGGTCTTATAACGCGGAACTGCTGGTTGCT ATGGAGAATCAGCATACCATCGACCTGGCTGACAGCGAGATGGATAAGTTATACGAGCGT GTCAAACGACAGCTGAGGGAGAATGCGGAGGAGGATGGAACCGGGTGTTTCGAGATCTTC CATAAATGTGACGATGACTGCATGGCCAGTATTCGGAACAATACATATGACCATTCCAAA TACCGCGAAGAGGCAATGCAGAATCGAATACAGATAGATCCTGTGAAACTGAGCAGCGGG TATAAAGACGTCATCTTGTGGTTTAGTTTTGGGGCATCCTGCTTTATTCTGCTCGCCATA GTGATGGGGTTAGTGTTTATATGTGTTAAAAACGGAAATATGCGGTGTACAATTTGTATC 624 ATGAATACCCAGATTCTTGTGTTTGCCCTGATCGCTATAATACCTACTAATGCAGATAAG ATCTGTTTAGGACATCACGCCGTCTCCAATGGAACTAAGGTAAACACGCTGACCGAGCGG GGCGTCGAGGTGGTGAACGCAACCGAAACTGTTGAGCGCACCAATATTCCCCGGATATGC TCAAAGGGGAAGCGAACCGTTGACCTAGGCCAATGCGGCTTGCTGGGGACAATTACCGGA CCACCCCAATGTGACCAGTTTCTGGAATTTTCAGCCGACCTAATCATCGAGCGACGCGAG GGCAGCGACGTGTGTTATCCCGGTAAGTTTGTCAATGAGGAAGCCCTGAGGCAGATACTT AGAGAATCGGGCGGGATCGACAAGGAGGCCATGGGGTTCACATATAGTGGTATCCGCACT AATGGAGCTACATCCGCCTGTCGGAGGAGCGGGAGCTCCTTCTACGCTGAAATGAAGTGG CTCCTCAGTAACACGGATAACGCTGCTTTCCCCCAGATGACTAAAAGCTATAAAAACACT AGAAAGAGCCCAGCACTCATTGTGTGGGGTATTCACCACTCAGTGTCTACGGCCGAACAA ACAAAATTATATGGATCCGGGAACAAGCTGGTAACCGTCGGAAGTAGCAATTATCAGCAG TCCTTTGTGCCAAGCCCGGGAGCCCGGCCCCAGGTGAACGGCCTATCTGGGCGGATCGAT TTTCATTGGCTTATGCTCAACCCTAACGACACCGTTACCTTTAGCTTCAACGGGGCTTTC ATTGCACCCGACCGTGCATCATTCCTGCGTGGGAAGAGCATGGGGATACAGAGCGGCGTA CAGGTGGACGCGAACTGCGAAGGCGACTGTTACCATTCAGGCGGCACCATTATTTCCAAT TTGCCGTTTCAGAACATCGACTCACGCGCCGTAGGAAAATGTCCCCGGTACGTCAAACAG CGCAGCCTCCTACTAGCCACCGGGATGAAAAACGTGCCCGAGATCCCCAAGGGACGGGGA CTATTCGGAGCGATAGCCGGGTTCATTGAGAATGGATGGGAGGGTCTGATCGATGGCTGG TACGGGTTCCGGCATCAAAACGCACAGGGCGAGGGGACTGCAGCCGATTACAAATCTACC CAATCGGCAATCGACCAGATTACAGGCAAACTGAATAGGATCATAGAGAAAACCAATCAG CAGTTCGAACTGATTGACAATGAGTTTAATGAAGTAGAGAAGCAGATTGGGAATGTGATA AATTGGACTCGAGACAGCATTACCGAAGTCTGGTCTTACAATGCCGAGTTACTCGTCGCT ATGGAGAACCAGCACACCATTGACCTGGCCGACTCAGAGATGGACAAACTCTATGAGCGC GTAAAGAGACAATTGAGGGAAAACGCGGAGGAAGACGGAACAGGCTGTTTCGAAATATTT CACAAGTGCGACGACGACTGTATGGCATCCATCCGGAATAATACCTATGATCACAGCAAG TACAGGGAGGAGGCTATGCAAAATCGGATCCAGATTGATCCTGTAAAACTGAGCTCGGGA TACAAGGATGTTATCCTGTGGTTTAGTTTCGGCGCCAGCTGCTTTATTCTCCTTGCCATC GTCATGGGCCTGGTCTTCATCTGCGTCAAAAATGGAAATATGAGATGCACAATTTGCATT 625 ATGAACACTCAAATTCTCGTGTTTGCTCTAATTGCCATCATCCCGACAAATGCAGATAAG ATTTGCCTGGGTCACCATGCGGTGTCTAATGGAACAAAGGTTAATACCCTGACCGAAAGG GGCGTGGAGGTCGTGAATGCCACCGAGACGGTGGAAAGAACCAACATTCCAAGAATTTGC TCCAAAGGAAAGAAAACCGTCGACCTGGGTCAGTGCGGATTGCTGGGAACAATCACCGGG CCACCCCAGTGCGACCAGTTCCTGGAATTCAGCGCCGACCTCATTATTGAGCGCAGAGAA GGTTCTGACGTGTGTTATCCAGGGAAGTTCGTGAACGAGGAGGCACTGCGGCAAATCCTG CGTGAAAGCGGCGGCATTGACAAGGAGGCGATGGGCTTTACATACTCCGGGATCCGTACA AACGGGGCCACTAGTGCGTGCAGAAGATCTGGAAGCAGCTTTTATGCTGAAATGAAATGG TTGCTCTCCAACACGGACAACGCTGCCTTCCCCCAGATGACAAAGAGCTACAAAAATACT CGAAAAAGCCCCGCCCTAATAGTGTGGGGCATCCACCATTCTGTGAGCACCGCCGAACAG ACCAAGCTGTATGGCAGCGGTAACAAATTGGTTACCGTAGGCTCTTCTAACTATCAGCAG AGCTTCGTCCCATCGCCTGGTGCCAGGCCCCAGGTCAACGGCCAAAGCGGTCGGATTGAT TTTCACTGGTTAATGCTTAATCCAAATGATACAGTGACCTTTAGTTTTAACGGAGCTTTC ATCGCCCCCGATCGGGCGAGCTTTCTCCGGGGGAAATCCATGGGAATCCAGTCTGGGGTG CAGGTGGACGCTAATTGCGAGGGCGACTGCTACCACTCCGGGGGGACCATCATAAGTAAC CTCCCTTTCCAAAACATCGATTCACGAGCTGTGGGAAAATGCCCCCGTTACGTAAAACAG CGTTCTCTCTTATTGGCCACAGGTATGAAAAATGTGCCAGAAATTCCTAAGGGCCGGGGG CTCTTCGGCGCCATAGCCGGATTCATTGAGAATGGGTGGGAAGGTCTGATCGACGGGTGG TACGGTTTCCGACACCAGAACGCACAGGGAGAGGGTACGGCTGCAGATTACAAGTCTACT CAGTCAGCTATTGACCAGATCACCGGCAAGCTGAATAGGCTTATCGAGAAAACAAACCAA CAGTTTGAACTGATCGACAATGAGTTTAACGAGGTCGAGAAGCAGATCGGCAACGTTATT AACTGGACTAGAGACTCCATCACCGAAGTGTGGAGCTACAATGCCGAGCTGCTAGTGGCT GGGGTAGAGGTGGTGAATGCTACAGAGACCGTTGAGCGCACTAACATCCCCAGAATATGT AGTAAAGGTAAGAAAACCGTCGACCTGGGCCAGTGTGGCCTGCTGGGCACAATTACCGGT CCACCCCAATGCGATCAGTTCTTAGAGTTCTCAGCAGATCTAATTATCGAGCGCCGCGAG GGGAGCGACGTCTGCTACCCTGGGAAATTTGTCAACGAAGAGGCCCTTCGGCAAATCCTT CGAGAGAGTGGCGGCATTGACAAGGAGGCAATGGGGTTTACTTATAGCGGAATCCGGACC AATGGAGCAACCTCTGCATGCAGGAGAAGCGGCAGTTCCTTCTATGCCGAAATGAAATGG CTGCTGAGCAATACAGATAACGCTGCCTTCCCACAGATGACCAAGAGTTACAAGAATACT AGGAAGTCCCCAGCCCTGATTGTTTGGGGAATTCACCACTCCGTTAGTACCGCCGAGCAA ACTAAACTGTACGGATCTGGAAACAAATTAGTTACAGTCGGAAGTTCTAACTACCAACAG TCATTTGTTCCATCTCCTGGTGCTAGGCCGCAGGTCAATGGCCAATCCGGCCGAATAGAC TTTCACTGGCTTATGCTTAATCCGAACGACACAGTGACCTTTAGCTTCAATGGCGCCTTC ATTGCCCCTGACAGAGCAAGCTTCCTGAGAGGCAAGAGCATGGGGATTCAGAGCGGTGTC CAGGTGGACGCTAACTGTGAGGGTGACTGCTATCACTCCGGTGGCACTATAATCTCTAAC CTACCCTTTCAGAATATCGACAGTCGGGCTGTGGGCAAGTGCCCCCGGTATGTTAAACAG CGTAGCCTTTTGCTGGCTACTGGGATGAAAAACGTGCCCGAGATACCCAAGGGGCGCGGA CTCTTCGGGGCCATCGCGGGCTTCATCGAGAATGGTTGGGAAGGTCTCATCGATGGCTGG TACGGATTCAGGCATCAGAACGCACAGGGTGAGGGGACAGCGGCTGACTACAAGTCGACC CAGAGTGCTATCGATCAGATAACTGGCAAGCTCAACCGGCTCATAGAGAAAACGAACCAG CAATTCGAGCTGATTGACAACGAATTCAACGAGGTTGAGAAGCAGATTGGCAATGTGATC AACTGGACGAGAGACAGCATTACCGAGGTGTGGAGTTACAACGCCGAGCTACTGGTAGCA ATGGAGAATCAACATACCATTGATTTGGCGGATTCTGAGATGGACAAGTTGTACGAGAGG GTCAAGCGGCAGCTGCGCGAAAACGCAGAAGAGGACGGCACTGGCTGCTTCGAGATTTTT CACAAATGTGATGACGATTGCATGGCGTCTATCAGGAATAACACATATGACCACAGCAAA TACCGGGAGGAAGCGATGCAGAACCGGATCCAAATTGATCCAGTCAAGCTGTCAAGCGGC TACAAGGATGTGATCTTATGGTTCAGTTTCGGAGCAAGTTGCTTTATTCTCCTTGCTATC GTTATGGGACTTGTCTTCATCTGTGTTAAAAACGGTAATATGCGGTGTACCATTTGTATT 633 ATGAACACCCAGATCCTGGTATTTGCTCTGATTGCCATCATTCCTACCAATGCCGACAAA ATCTGTCTGGGCCACCACGCAGTTTCGAATGGCACTAAAGTGAATACCCTGACCGAGCGC GGCGTCGAGGTCGTGAATGCCACAGAGACCGTCGAACGCACAAATATACCTCGGATTTGC AGCAAGGGAAAGCGGACAGTGGACCTCGGGCAGTGCGGACTGCTCGGGACTATAACTGGA CCGCCTCAGTGCGATCAATTTTTGGAGTTTTCCGCTGATTTGATCATCGAGAGAAGAGAA GGAAGCGACGTCTGCTATCCAGGAAAGTTCGTGAACGAGGAGGCCCTGAGGCAAATCTTG AGGGAGAGTGGTGGCATCGACAAAGAGGCTATGGGTTTCACCTACTCAGGTATACGCACC AACGGCGCAACAAGTGCTTGTCGGCGGTCAGGATCTTCCTTCTACGCCGAGATGAAATGG TTGCTAAGTAATACAGACAATGCTGCGTTCCCTCAGATGACAAAGTCCTATAAGAATACA CGGAAGTCACCTGCCCTGATCGTGTGGGGCATTCACCACAGCGTTAGCACAGCTGAGCAG ACCAAGTTATATGGCAGTGGTAACAAACTCGTAACGGTGGGGAGTTCCAATTACCAACAG AGCTTCGTGCCGTCTCCTGGAGCTCGTCCACAGGTCAACGGACTGAGTGGGCGCATTGAC TTCCATTGGCTTATGTTAAACCCTAATGACACCGTGACGTTTAGCTTCAACGGCGCTTTT ATCGCCCCTGACCGGGCCTCATTTCTGAGGGGAAAGAGCATGGGGATCCAGTCCGGAGTG CAGGTGGATGCTAATTGCGAAGGGGACTGCTATCACAGCGGAGGCACCATCATTTCGAAT CTCCCATTCCAGAACATCGACTCTAGGGCTGTGGGCAAGTGCCCTCGATATGTGAAACAG CGGAGCTTGCTGCTTGCTACCGGGATGAAGAACGTGCCGGAGATCCCCAAGGGCCGTGGC TTATTTGGCGCTATCGCGGGTTTCATCGAAAATGGTTGGGAGGGCCTAATAAACGGCTGG TACGGTTTCCGCCACCAGAACGCGCAGGGCGAGGGGACCGCCGCCGATTACAAATCCACA CAGAGCGCAATCGATCAAATAACTGGAAAGCTGAATCGCTTGATCGAAAAGACCAATCAG CAGTTTGAGCTAATCGATAACGAATTTAATGAAGTGGAAAAGCAAATCGGAAACGTGATC AATTGGACCAGAGACTCGATAACAGAGGTGTGGAGTTACAATGCAGAGCTGCTGGTAGCC ATGGAAAATCAGCACACGATTGACCTGGCAGATTCAGAGATGGATAAGCTGTACGAGAGG GTGAAGAGGCAGCTCCGTGAGAATGCTGAAGAGGATGGAACCGGGTGTTTCGAGATTTTT CACAAATGCGACGACGATTGTATGGCCTCCATCAGGAATAACACATACGACCATAGCAAA TACAGAGAGGAGGCAATGCAAAATCGGATTCAAATTGATCCCGTGAAACTTTCTAGCGGG TACAAGGATGTTATCTTGTGGTTCAGTTTCGGCGCCTCCTGTTTTATTCTGCTGGCAATT GTGATGGGTCTGGTGTTTATTTGTGTAAAGAACGGGAATATGAGGTGCACAATTTGCATC 634 ATGAACACTCAGATACTGGTTTTCGCTTTGATCGCTATCATACCCACAAATGCCGACAAG ATATGCTTGGGTCATCACGCCGTGTCCAACGGCACTAAAGTGAACACATTGACCGAGAGA GGAGTAGAAGTGGTCAATGCTACAGAGACCGTGGAACGCACTAATATCCCGCGGATATGT AGTAAGGGCAAAAAAACCGTGGACCTCGGCCAGTGTGGCCTGCTGGGCACCATTACCGGC CCGCCACAATGTGATCAGTTCTTGGAATTCTCTGCAGACCTTATCATAGAGCGCCGGGAA ATGGAGAATCAACATACCATTGATCTGGCCGATAGTGAGATGGACAAGCTGTATGAACGA GTCAAGCGACAACTACGCGAAAATGCGGAAGAAGATGGGACAGGATGTTTTGAGATTTTC CACAAATGCGATGACGATTGTATGGCCAGCATCCGGAACAACACATACGATCATAGCAAA TACAGAGAGGAGGCCATGCAAAATCGCATTCAAATAGACCCTGTCAAGCTTAGCTCCGGG TATAAAGACGTGATTCTATGGTTCTCGTTTGGGGCCTCATGTTTCATTCTGCTGGCCATC GTCATGGGCCTCGTGTTTATTTGCGTAAAGAATGGCAACATGCGCTGTACCATCTGTATT 626 ATGAACACTCAGATTCTGGTGTTTGCTCTGATCGCGATTATCCCCACTAATGCCGACAAG ATATGTCTCGGTCATCATGCGGTTTCTAACGGGACGAAGGTGAACACATTGACAGAGCGA GGGGTGGAGGTGGTTAATGCGACTGAGACTGTAGAAAGGACCAATATTCCGCGTATTTGT AGCAAGGGTAAGAAAACTGTTGACTTGGGACAATGTGGTCTGCTCGGAACCATTACTGGC CCCCCTCAGTGTGATCAATTCCTGGAGTTCAGCGCCGATCTGATTATAGAGCGAAGAGAG GGTAGCGATGTTTGCTATCCCGGGAAATTTGTAAACGAGGAGGCCCTCCGCCAAATCCTA CGAGAGTCAGGTGGGATTGACAAGGAGGCTATGGGGTTCACCTATAGTGGAATCCGGACC AATGGGGCAACTTCTGCCTGTCGGAGATCTGGCTCGAGCTTCTACGCGGAGATGAAGTGG TTGCTGAGTAACACTGATAACGCTGCGTTTCCCCAAATGACCAAGTCGTATAAAAATACA AGAAAGAGTCCTGCTCTGATCGTGTGGGGAATCCATCACTCTGTAAGCACGGCCGAGCAA ACTAAACTTTATGGATCGGGCAATAAACTTGTCACAGTGGGCAGCAGCAACTACCAGCAA TCATTTGTGCCTTCTCCGGGCGCGAGACCACAGGTCAATGGCCAGTCTGGGAGGATCGAT TTTCACTGGCTCATGCTAAATCCCAACGACACAGTGACCTTTAGCTTTAATGGCGCATTT ATTGCACCTGATAGAGCGTCATTCCTTAGGGGAAAAAGCATGGGGATACAATCAGGGGTC CAGGTCGACGCTAATTGCGAGGGCGACTGCTACCACTCAGGGGGTACCATCATATCTAAT CTTCCATTCCAGAACATCGACTCGCGAGCCGTTGGAAAGTGCCCCAGGTACGTGAAGCAG CGGAGTCTGCTCCTGGCAACTGGCATGAAGAACGTGCCTGAGATCCCCAAAGGCCGTGGC TTATTTGGAGCTATCGCAGGGTTTATCGAGAATGGCTGGGAGGGATTGATCGATGGTTGG TATGGCTTTCGGCACCAAAATGCCCAGGGAGAGGGAACCGCCGCCGATTATAAGTCAACT CAGAGTGCGATAGATCAGATTACAGGTAAGCTAAATAGACTGATTGAGAAGACTAACCAA CAGTTCGAGCTTATCGACAACGAATTTAATGAAGTGGAAAAGCAAATAGGAAACGTTATC AACTGGACACGCGATAGCATCACAGAAGTTTGGTCTTACAACGCCGAGCTCTTGGTGGCT ATGGAGAATCAACATACAATCGACCTGGCAGATAGCGAAATGGATAAGTTATACGAACGG GTCAAGCGACAGCTGAGGGAGAACGCTGAAGAGGATGGAACTGGCTGTTTTGAGATCTTC CACAAGTGCGATGATGACTGTATGGCAAGCATACGAAACAACACTTACGATCATTCAAAG TACCGGGAGGAGGCCATGCAAAACAGGATTCAGATTGATCCAGTGAAGTTGTCCTCTGGC TACAAGGATGTGATACTGTGGTTTTCCTTCGGAGCAAGCTGCTTTATCTTACTGGCAATT GTGATGGGACTCGTGTTTATATGCGTGAAAAATGGAAATATGCGCTGTACAATCTGCATC 627 ATGAACACGCAGATACTTGTGTTTGCCCTTATTGCCATTATTCCCACTAACGCGGACAAA ATATGCCTGGGCCATCACGCTGTCTCCAATGGGACGAAAGTGAACACATTGACCGAGCGA GGCGTGGAAGTGGTAAATGCGACCGAAACCGTAGAGAGAACCAACATTCCTAGAATTTGC TCCAAGGGCAAACGGACAGTAGATCTGGGGCAGTGCGGACTGTTGGGTACAATTACAGGA CCTCCCCAGTGCGATCAGTTCCTGGAGTTTTCCGCTGATCTGATTATAGAAAGGCGAGAG GGTTCCGACGTGTGCTACCCTGGTAAGTTTGTTAAAGAGGAAGCTCTCCGTCAGATTCTC CGAGAGTCTGGCGGGATCGATAAAGAGGCGATGGGGTTTACCTACTCTGGAATAAGGACC AACGGAGCAACCTCCGCCTGCAGGAGATCAGGGTCGTCCTTCTATGCTGAAATGAAATGG TTGCTGTCTAATACCGACAATGCAGCCTTCCCCCAGATGACCAAAAGCTACAAGAATACA CGCAAATCTCCCGCCCTGATTGTGTGGGGCATACACCATAGTGTGAGTACTGCAGAACAG ACCAAGCTTTACGGATCCGGCAATAAGCTGGTGACTGTAGGCTCTAGCAACTACCAACAG AGCTTTGTACCATCCCCCGGTGCACGCCCTCAGGTGAACGGACTCTCGGGGCGGATAGAT TTCCACTGGTTGATGTTGAATCCCAACGACACCGTGACGTTCAGTTTCAACGGTGCTTTC ATCGCGCCTGATAGGGCCTCTTTCTTAAGAGGGAAATCAATGGGCATCCAGAGCGGGGTT CAGGTAGACGCTAACTGTGAGGGTGACTGCTATCATAGCGGCGGCACTATTATATCTAAC CTGCCCTTCCAGAATATCGACTCCCGGGCCGTGGGAAAATGCCCAAGGTATGTGAAACAG AGGTCACTGCTACTGGCGACCGGGATGAAGAACGTTCCAGAAATACCTAAAGGTCGTGGG CTGTTCGGCGCAATTGCCGGTTTCATTGAAAACGGCTGGGAGGGCCTGATCGACGGATGG TATGGGTTCAGACACCAGAACGCCCAGGGAGAGGGCACAGCTGCCGACTATAAGTCCACA CAAAGCGCCATTGATCAGATCACAGGCAAGCTTAACAGACTGATCGAGAAGACAAACCAG CAATTTGAGTTGATAGACAACGAGTTCAACGAAGTGGAGAAGCAAATCGGGAACGTCATT AATTGGACCCGGGATTCTATCACCGAAGTATGGTCATACAACGCCGAGCTGCTCGTGGCT ATGGAGAATCAGCATACCATTGATCTTGCCGATTCCGAGATGGACAAGCTGTATGAAAGA GTCAAACGACAGTTGCGAGAAAACGCTGAAGAGGACGGAACAGGATGCTTTGAAATCTTT CACAAATGTGACGACGACTGTATGGCAAGCATTCGGAACAATACCTATGATCACTCAAAG TACCGAGAGGAGGCCATGCAGAATAGGATTCAGATCGACCCAGTCAAGCTCTCCTCCGGG TACAAAGATGTAATCCTGTGGTTTTCGTTCGGCGCCAGTTGTTTCATCTTACTGGCCATA GTCATGGGCCTGGTCTTTATCTGCGTTAAGAACGGCAACATGCGCTGCACTATTTGCATC 628 ATGAACACCCAGATACTTGTTTTTGCCCTGATTGCCATCATCCCAACCAACGCCGACAAG ATCTGCTTGGGGCACCATGCTGTTAGCAACGGAACAAAAGTGAACACCCTGACCGAAAGA GGCGTCGAGGTAGTAAACGCCACTGAAACGGTCGAGCGAACCAATATACCTAGGATATGT TCAAAGGGAAAAAGGACGGTTGATTTAGGTCAGTGTGGACTTCTGGGGACAATCACCGGA CCACCCCAATGTGACCAGTTCCTTGAGTTCAGCGCGGACCTGATTATTGAGAGACGTGAA GGATCTGACGTCTGCTACCCAGGAAAGTTTGTGAATGAGGAAGCACTCCGCCAGATTCTC AGGGAATCCGGCGGCATTGATAAAGAGGCAATGGGATTTACCTACTCCGGCATTCGGACT AACGGTGCTACATCTGCATGTAGACGGTCCGGCTCTTCATTCTATGCAGAGATGAAATGG CTGCTTTCAAATACTGATAACGCCGCCTTTCCTCAGATGACCAAATCCTACAAGAACACC CGGAAATCCCCCGCCCTCATTGTTTGGGGGATCCACCACTCAGTGTCAACCGCCGAGCAG ACCAAGCTCTACGGAAGTGGAAATAAGTTGGTAACTGTGGGAAGCTCTAACTACCAGCAA AGCTTTGTGCCAAGTCCTGGAGAGAGGCCCCAGGTGAACGGACTTAGCGGTAGGATCGAT TTTCATTGGCTTATGCTCAACCCCAACGATACGGTCACCTTTTCATTCAATGGGGCCTTT ATTGCACCGGATAGAGCCAGCTTTCTGAGAGGGAAGTCTATGGGCATCCAGTCGGGCGTA CAGGTGGATGCAAACTGTGAGGGGGATTGCTATCATAGTGGAGGCACCATCATAAGTAAT CTGCCCTTCCAGAATATCGATAGCCGGGCCGTGGGCAAATGTCCAAGGTATGTGAAACAG AGGTCACTGCTGCTCGCTACAGGCATGAAAAACGTGCCTGAAATACCCAAAGGACGGGGG CTTTTCGGCGCCATCGCCGGCTTCATTGAGAACGGATGGGAAGGTTTGATCGATGGATGG TATGGATTTAGGCACCAAAACGCCCAGGGGGAAGGCACCGCCGCGGACTACAAGAGTACT CAGTCTGCAATCGACCAAATCACTGGCAAACTGAATCGGCTGATTGAGAAGACCAATCAG CAATTCGAACTCATTGACAACGAGTTTAATGAAGTGGAGAAACAGATCGGTAACGTGATA AATTGGACCAGAGACTCGATCACGGAAGTATGGAGCTACAATGCTGAACTGTTGGTCGCT ATGGAGAATCAACACACTATCGACCTGGCCGACAGCGAGATGGATAAACTCTATGAAAGA GTGAAACGGCAGCTCAGAGAGAACGCAGAGGAGGACGGAACCGGCTGCTTTGAAATATTC CATAAATGCGACGACGATTGCATGGCCAGCATCAGGAACAATACCTATGATCATAGCAAG TACCGGGAGGAAGCCATGCAGAATAGAATTCAGATCGACCCAGTGAAACTGTCTAGCGGA TATAAGGACGTGATTCTGTGGTTCTCATTCGGCGCCTCATGCTTCATTCTATTGGCGATT GTGATGGGACTTGTGTTCATCTGCGTCAAAAATGGCAATATGCGGTGCACGATATGTATC 629 ATGAACACCCAAATTCTGGTCTTTGCTCTGATCGCAATTATCCCAACCAATGCTGACAAA ATTTGCCTCGGACATCATGCGGTATCCAACGGCACAAAGGTAAACACTCTCACTGAACGC GGAGTTGAGGTGGTAAATGCCACGGAAACAGTTGAGAGGACTAATATACCTAGAATTTGT AGCAAAGGAAAAAAAACGGTGGACCTCGGGCAGTGTGGCCTGCTTGGAACAATTACAGGC CCGCCCCAGTGCGACCAGTTCCTAGAATTCTCCGCCGATCTGATCATCGAACGCCGCGAA GGAAGCGATGTGTGTTATCCAGGCAAGTTTGTGAATGAGGAGGCCCTGAGACAAATCCTG CGGGAGAGCGGCGGAATTGATAAAGAGGCAATGGGATTCACTTACAGTGGGATCCGGACA AACGGGGCCACGTCGGCCTGCAGACGTAGCGGGAGTTCCTTCTATGCCGAAATGAAGTGG CTGCTGTCCAACACTGACAACGCGGCCTTTCCACAAATGACTAAATCTTATAAAAACACA CGGAAGTCACCAGCTCTCATCGTGTGGGGTATCCACCATTCGGTCTCTACAGCTGAGCAA ACTAAGCTTTACGGAAGTGGCAACAAACTGGTGACAGTGGGCAGCTCTAACTACCAGCAG TCATTTGTCCCGTCTCCCGGGGCCAGACCACAGGTTAATGGGCAGTCAGGCCGGATCGAT TTTCATTGGTTGATGTTAAACCCAAACGACACAGTCACATTTAGTTTTAATGGGGCATTT ATAGCCCCTGATAGAGCTAGTTTCTTGAGGGGAAAGAGTATGGGGATCCAGTCAGGTGTA CAGGTCGACGCCAACTGCGAGGGTGACTGTTACCATTCCGGGGGTACCATCATTAGTAAC CTGCCTTTCCAGAACATCGACAGTAGAGCAGTGGGTAAATGCCCAAGGTACGTGAAACAA CGCAGCTTACTGCTGGCTACAGGAATGAAAAACGTGCCCGAGATTCCAAAAGGGAGGGGT TTGTTCGGTGCTATTGCCGGTTTTATTGAAAACGGATGGGAGGGTCTCATCGATGGATGG TATGGGTTTAGGCACCAGAATGCACAAGGGGAAGGAACTGCCGCCGATTATAAATCCACC CAGTCCGCTATTGACCAGATTACCGGTAAACTGAATCGTTTGATTGAGAAAACAAACCAG CAGTTTGAACTAATCGACAACGAATTCAATGAAGTGGAGAAGCAGATTGGTAACGTCATT AACTGGACCCGTGACAGTATCACTGAAGTTTGGTCTTATAATGCCGAACTCCTAGTAGCG ATGGAGAACCAGCACACCATAGACCTCGCCGATAGTGAAATGGACAAACTGTATGAGAGA GTGAAGCGGCAGTTACGCGAAAACGCTGAGGAGGACGGGACTGGCTGCTTCGAGATTTTT CACAAGTGCGACGACGACTGCATGGCATCAATCCGCAACAATACATACGATCATTCCAAG TATCGTGAAGAAGCCATGCAGAACCGGATCCAAATAGACCCTGTCAAACTTAGCAGCGGG TATAAAGATGTTATTCTGTGGTTTAGCTTTGGAGCCAGTTGTTTCATACTGCTGGCCATT GTTATGGGCCTCGTCTTCATCTGCGTGAAAAACGGGAACATGCGATGTACGATCTGCATT 630 ATGAACACTCAAATTTTAGTCTTCGCCCTCATTGCGATAATCCCTACTAACGCAGACAAG ATCTGTCTGGGACACCACGCCGTGTCTAATGGCACCAAAGTGAACACATTGACGGAGAGA GGAGTAGAGGTGGTGAACGCCACCGAGACCGTCGAGAGAACCAATATACCTAGGATCTGC AGCAAGGGAAAGAAGACTGTCGATCTGGGCCAATGCGGGTTGCTCGGGACTATTACTGGA CCTCCGCAATGTGACCAGTTCCTTGAATTCTCTGCTGACCTGATAATCGAACGACGAGAG GGATCCGATGTTTGCTATCCAGGGAAGTTTGTGAATGAGGAGGCTCTCAGACAAATCCTG CGGGAGTCCGGCGGCATCGACAAAGAAGCCATGGGTTTCACCTATAGTGGAATTCGGACC AATGGCGCAACCAGCGCATGCCGGCGTAGTGGAAGCTCCTTTTATGCCGAGATGAAGTGG TTACTTTCCAATACCGATAACGCAGCATTCCCTCAGATGACCAAAAGTTACAAGAACACT CGTAAATCTCCTGCTCTTATTGTATGGGGGATACACCACAGTGTGAGCACCGCCGAGCAA ACTAAGCTTTACGGATCAGGGAATAAGCTTGTAACAGTGGGAAGCTCTAACTACCAACAG TCCTTTGTTCCATCTCCCGGGGCGAGACCTCAAGTAAACGGGCAATCTGGTAGGATAGAC TTTCATTGGCTGATGCTGAATCCGAATGATACAGTTACCTTCTCCTTTAATGGAGCCTTT ATCGCCCCCGACAGAGCGAGTTTTCTGAGGGGGAAGTCTATGGGGATCCAGTCCGGCGTT CAGGTAGACGCGAATTGCGAAGGGGATTGCTATCACAGCGGCGGTACAATTATCTCTAAC CTCCCTTTCCAGAATATCGACTCCCGAGCCGTTGGGAAGTGCCCTCGGTATGTTAAGCAA CGGAGCCTGCTGCTGGCTACCGGGATGAAAAACGTGCCTGAGATTCCTAAAGGCCGGGGC CTATTTGGGGCCATCGCTGGTTTTATAGAGAACGGCTGGGAAGGTCTGATCGATGGCTGG TATGGTTTTAGACATCAGAATGCCCAGGGTGAAGGGACCGCCGCCGACTACAAGAGTACC CAATCTGCCATCGACCAGATCACCGGGAAGCTGAACCGTCTCATCGAGAAGACGAACCAG CAGTTCGAACTGATTGATAATGAGTTCAATGAAGTGGAGAAGCAGATCGGTAACGTTATC AACTGGACGCGCGACAGCATAACCGAGGTGTGGAGTTATAACGCTGAACTCTTGGTTGCC ATGGAGAACCAGCATACCATCGATCTCGCCGATAGTGAGATGGATAAGCTGTATGAACGG GTGAAAAGGCAACTGCGCGAGAACGCCGAGGAAGACGGCACCGGCTGCTTTGAAATCTTT CACAAATGCGATGATGATTGTATGGCATCTATCAGGAACAATACCTACGATCACAGCAAA TACCGCGAGGAAGCCATGCAGAATAGAATCCAGATAGATCCCGTGAAGCTGTCCAGCGGG TATAAGGACGTCATCTTGTGGTTCAGTTTTGGGGCTTCGTGTTTTATTCTGTTGGCTATC GTCATGGGCCTCGTGTTCATCTGCGTCAAGAACGGGAACATGCGCTGCACCATCTGCATA 631 ATGAACACTCAAATTTTAGTCTTTGCATTAATTGCCATTATCCCAACCAACGCAGACAAA ATCTGCCTGGGACATCACGCCGTGTCAAACGGCACCAAAGTGAACACGCTGACCGAACGT GGGGTCGAAGTGGTGAATGCCACAGAGACTGTCGAGCGCACAAATATCCCGCGCATTTGT TCCAAGGGTAAGCGGACGGTGGACTTAGGTCAGTGTGGACTTCTAGGTACTATTACCGGA CCTCCACAGTGTGACCAGTTCCTGGAGTTCTCTGCCGATCTCATCATTGAGCGTCGCGAA GGAAGTGATGTCTGTTACCCAGGAAAATTCGTGAATGAAGAAGCCCTCCGGCAAATTCTG CGCGAGTCCGGGGGCATCGACAAGGAGGCGATGGGCTTCACCTATAGTGGCATCCGAACA AACGGCGCCACCTCCGCATGCCGGAGGAGTGGCAGCTCCTTCTACGCCGAGATGAAGTGG CTCTTATCCAACACAGACAATGCCGCTTTCCCGCAGATGACAAAGAGTTACAAAAACACG CGGAAAAGTCCCGCTTTGATTGTGTGGGGTATCCACCACTCTGTCTCTACAGCGGAGCAG ACAAAGTTATACGGGTCTGGCAGTAAACTGGTTACAGTGGGCTCAAGCAACTACCAACAG TCTTTCGTCCCCTCCCCTGGCGCAAGACCCCAGGTAAATGGCCTCTCTGGAAGGATTGAC TTCCACTGGCTGATGCTCAACCCAAATGATACCGTGACATTTAGCTTCAACGGTGCATTT ATCGCCCCAGACAGAGCTAGTTTCCTTCGGGGCAAATCAATGGGGATTCAGAGCGGAGTG CAGGTGGATGCTAATTGTGAAGGCGATTGCTACCACTCCGGCGGTACTATTATCTCAAAC CTGCCTTTTCAGAATATCGATAGTAGAGCCGTGGGCAAGTGCCCGCGTTATGTGAAACAG CGCTCTCTTTTGCTCGCTACAGGAATGAAAAACGTACCAGAGATCCCCAAGGGGCGTGGC CTATTTGGAGCTATCGCTGGTTTTATTGAAAACGGGTGGGAGGGCCTGATAGACGGTTGG TATGGCTTCAGACACCAGAATGCTCAGGGAGAGGGCACCGCCGCCGACTATAAATCAACA CAGAGTGCGATCGACCAGATTACCGGAAAACTGAATCGCCTCATAGAGAAGACAAACCAA CAGTTCGAGCTCATCGACAACGAATTTAACGAGGTAGAAAAACAGATCGGTAACGTTATC AACTGGACACGGGACAGCATCACGGAGGTGTGGTCTTACAATGCCGAGCTTTTGGTGGCT ATGGAGAACCAGCACACAATCGACCTCGCCGATAGTGAAATGGATAAACTTTATGAGAGG GTAAAGCGTCAGCTGCGAGAGAATGCTGAAGAAGATGGGACAGGTTGCTTTGAGATCTTC CACAAGTGCGATGACGATTGCATGGCCTCTATTAGAAATAACACTTACGATCATAGCAAA TATAGAGAGGAAGCTATGCAGAATAGGATCCAGATAGATCCCGTAAAGCTGTCCTCTGGA TATAAGGACGTGATCCTCTGGTTCAGTTTTGGGGCATCATGTTTTATTCTGCTCGCAATC GTTATGGGTTTAGTTTTCATTTGTGTCAAATCACGGAATATGAGATGTACAATCTGTATT 632 ATGAATACACAGATCCTGGTGTTCGCACTGATCGCTATCATCCCCACAAACGCTGACAAA ATCTGTCTGGGGCACCACGCGGTGAGTAACGGCACTAAGGTGAATACACTGACCGAACGC GGATCTGACGTGTGTTATCCAGGCAAGTTCGTTAACGAGGAGGCCCTTAGGCAGATTTTG CGTGAGAGCGGAGGCATCGATAAAGAAGCTATGGGGTTTACATATAGCGGTATTCGAACA AACGGAGCCACCTCTGCATGCAGGCGGTCCGGGTCATCATTCTACGCGGAGATGAAGTGG CTGCTCTCAAATACGGACAATGCGGCATTTCCCCAGATGACAAAAAGTTACAAAAACACA AGGAAATCCCCAGCCCTGATCGTGTGGGGAATTCACCACAGTGTTAGCACCGCTGAGCAG ACCAAACTCTATGGCTCTGGCAACAAATTAGTTACCGTCGGATCAAGTAATTACCAGCAG TCTTTTGTCCCGAGCCCAGGGGCTAGACCTCAGGTGAATGGACAGTCCGGAAGGATCGAC TTCCACTGGCTGATGCTTAATCCAAACGATACAGTTACTTTCTCATTCAATGGCGCCTTC ATCGCTCCCGATAGAGCTTCTTTCTTGCGAGGCAAATCAATGGGCATCCAGAGCGGGGTG CAGGTCGATGCAAATTGTGAGGGTGATTGCTATCATTCAGGCGGTACCATCATATCCAAT CTCCCTTTCCAAAACATTGATTCCCGGGCAGTGGGAAAATGTCCCCGCTATGTGAAACAG AGGTCACTTCTATTAGCCACAGGGATGAAAAATGTGCCAGAGATTCCCAAAGGAAGGGGC CTCTTTGGCGCAATCGCAGGTTTCATCGAGAATGGTTGGGAGGGTCTGATCGACGGCTGG TACGGCTTCAGGCACCAGAACGCTCAGGGGGAGGGCACCGCAGCCGATTATAAAAGCACC CAAAGTGCTATTGATCAGATCACAGGCAAACTGAACCGGCTTATAGAGAAGACAAATCAG CAGTTTGAGTTAATAGACAACGAATTCAACGAGGTGGAGAAACAGATTGGAAACGTTATA AACTGGACTCGGGACTCTATTACCGAGGTTTGGTCTTACAACGCCGAACTCCTAGTGGCC ATGGAGAATCAGCATACCATCGATCTCGCTGATTCTGAAATGGACAAGCTGTACGAGAGG GTTAAACGGCAGCTGCGAGAGAATGCAGAGGAAGACGGAACAGGCTGCTTCGAGATCTTC CACAAATGCGATGACGATTGTATGGCTTCCATCCGCAATAACACCTACGACCACAGCAAG TATCGGGAAGAAGCCATGCAGAACCGCATTCAAATTGACCCGGTAAAACTTTCCAGCGGA TACAAGGACGTCATCCTGTGGTTTAGTTTCGGTGCGAGCTGCTTCATCTTACTAGCTATC GTGATGGGCCTCGTGTTCATCTGCGTTAAAAACGGCAACATGCGTTGTACCATATGTATT 635 ATGAACACACAGATCCTCGTTTTCGCTCTGATAGCAATTATCCCAACAAACGCAGACAAA ATCTGTCTGGGGCACCATGCCGTGAGTAACGGCACTAAGGTCAATACACTGACAGAGCGC GGCGTGGAGGTTGTCAATGCTACAGAAACTGTTGAGAGAACGAACATACCTCGGATTTGC AGCAAGGGCAAAAAGACCGTCGACCTGGGCCAGTGTGGCTTGCTCGGAACCATCACCGGC CCACCCCAATGCGACCAGTTCCTTGAATTCAGTGCGGACCTCATCATCGAAAGGAGAGAA GGAAGTGATGTGTGCTATCCCGGGAAGTTCGTGAACGAAGAGGCCCTGAGGCAGATTCTT CGGGAGTCTGGTGGTATCGAAAAGGAGGCCATGGGATTCACCTACAGCGGCATTCGCGCC AACGGTGCAACTTCTGCATGTCGCCGCTCTGGGTCTTCTTTTTACGCCGAAATGAAGTGG CTGCTTTCTAATACAGATAATGCGGCATTCCCACAAATGACCAAGTCATATAAAAACACG AGAAAGAGTCCCGCCCTTATAGTGTGGGGGATTCACCACTCCGTCTCCACAGCTGAACAG ACAAAATTATACGGCAGTGGGAATAAGCTTGTTACTGTCGGCTCCAGCAATTATCAGCAA AGCTTCGTGCCATCCCCAGGGGCCAGACCACAGGTAAACGGGCTCAGCGGACGCATCGAT TTTCATTGGTTGATGCTAAACCCAAACGACACCGTAACATTTAGTTTCAACGGTGCCTTC ATAGCGCCCGATCGGGCATCGTTCCTGCGGGGAAAATCCATGGGCATTCAAAGCGGCGTG CAGGTGGACGCGAATTGCGAAGGTGACTGTTATCATAGCGGCGGGACCATTATAAGCAAT CTGCCTTTTCAGAACATCGACTCACGGGCCGTGGGCAAATGCCCTCGTTACGTGAAACAA CGAAGCCTGCTGCTGGCGACCGGAATGAAAAATGTCCCGGAAATACCTAAAGGAAGGGGG CTCTTCGGGGCTATAGCCGGTTTTATCGAGAACGGCTGGGAGGGCCTGATCGATGGATGG TACGGGTTCAGGCACCAGAACGCCCAAGGGGAAGGCACGGCCGCGGACTATAAGTCAACT CAGTCTGCCATTGACCAGATTACTGGGAAGCTCAATCGCCTGATCGAAAAGACCAACCAG CAATTTGAGTTGATCGACAATGAGTTTAATGAAGTGGAAAAACAGATCGGGAATGTGATC AACTGGACCAGGGACTCTATTACCGAGGTTTGGTCCTACAACGCAGAGTTACTCGTAGCC ATGGAAAACCAACACACCATTGACCTCGCCGATAGTGAGATGGATAAACTGTATGAACGC GTCAAGCGGCAGTTGCGAGAAAATGCAGAAGAGGATGGCACAGGGTGTTTTGAGATTTTC CATAAGTGCGACGATGACTGTATGGCCTCCATCCGCAATAACACCTACGATCACTCAAAG TACCGGGAAGAGGCCATGCAGAATCGAATTCAGATTGACCCAGTTAAACTATCTTCAGGG TACAAAGATGTGATTCTATGGTTTAGTTTTGGTGCATCGTGCTTTATCCTCCTGGCTATC GTTATGGGCCTCGTCTTTATCTGTGTCAAGAACGGGAATATGAGATGTACTATTTGCATC 636 ATGAACACCCAGATTCTAGTATTCGCCCTGATTGCAATAATCCCAACAAATGCAGATAAA ATCTGTCTGGGACACCACGCGGTCTCAAACGGGACTAAGGTTAATACCCTCACGGAAAGA GGAGTGGAGGTGGTGAACGCTACGGAGACCGTCGAGCGTACAAACATACCCCGGATCTGC TCAAAAGGCAAGAGGACCGTGGATTTAGGACAGTGCGGATTGTTGGGAACAATCACCGGC CCTCCTCAGTGTGACCAATTTCTCGAGTTTAGTGCCGATCTGATTATCGAACGGCGCGAG GGATCAGACGTGTGCTACCCGGGGAAATTCGTAAACGAGGAGGCTCTGCGCCAGATTCTC CGGGAGTCCGGGGGGATTGATAAGGAGGCCATGGGGTTCACATATTCTGGCATTCGGACC AATGGCGCCACTTCTGCCTGCAGACGCTCCGGCTCGAGCTTTTATGCCGAAATGAAATGG CTCCTTAGCAACACCGATAATGCCGCATTCCCCCAAATGACCAAAAGTTACAAGAATACA CGTAAGTCGCCTGCACTTATCGTGTGGGGCATACACCACTCAGTGAGCACAGCTGAGCAA ACCAAGTTATATGGTTCGGGGAGTAAGCTGGTGACCGTAGGGTCTTCAAATTATCAGCAG AGTTTCGTCCCTAGTCCAGGCGCCAGGCCTCAGGTTAACGGTCTGTCTGGACGCATCGAT TTTCATTGGTTGATGCTTAATCCGAACGATACAGTGACTTTCTCTTTTAATGGCGCCTTC ATCGCCCCCGATCGCGCTAGCTTCCTCCGGGGTAAAAGCATGGGTATCCAGAGCGGCGTG CAGGTTGACGCCAACTGCGAGGGAGACTGCTATCACAGCGGCGGTACCATCATCTCCAAC CTTCCCTTTCAGAACATAGACTCTCGGGCTGTCGGAAAATGTCCTCGATACGTGAAGCAG AGATCACTGCTGCTTGCTACTGGAATGAAGAACGTCCCCGAGATACCGAAAGGGAGAGGT CTCTTTGGTGCTATAGCAGGGTTTATTGAAAACGGGTGGGAAGGCTTGATCGACGGTTGG TATGGCTTCAGACATCAGAATGCTCAGGGCGAGGGCACAGCAGCAGATTATAAGTCGACA CAGAGTGCAATCGATCAGATTACTGGCAAACTGAATAGGCTTATTGAGAAGACCAATCAG CAATTTGAGCTTATCGACAACGAGTTTAACGAAGTTGAAAAGCAAATTGGGAACGTCATC AACTGGACCCGGGACTCAATCACCGAAGTATGGAGCTATAATGCCGAGTTGCTGGTTGCA ATGGAGAACCAGCACACTATCGATCTTGCGGATTCCGAAATGGATAAACTTTACGAAAGA GTGAAGAGACAGCTCAGAGAAAACGCCGAGGAGGACGGTACGGGTTGTTTTGAGATATTC CACAAGTGCGATGATGATTGCATGGCTAGCATCAGGAACAACACCTATGATCACAGCAAA TACCGTGAGGAGGCAATGCAGAACAGGATTCAGATTGACCCTGTGAAACTGTCTAGCGGC TACAAGGACGTGATCTTGTGGTTTTCTTTCGGTGCCAGTTGTTTTATCTTACTCGCCATT GTCATGGGGCTCGTTTTCATTTGTGTAAAAAATGGAAACATGAGGTGTACGATTTGTATA 637 ATGAACACACAAATTCTCGTGTTTGCCCTAATCGCCATTATCCCGACAAACGCAGATAAG ATCTGTCTGGGGCACCACGCAGTCAGCAATGGCACCAAAGTGAATACTCTTACCGAGAGA GGAGTGGAAGTCGTGAATGCCACGGAGACCGTCGAGAGGACTAATATCCCAAGGATTTGT AGCAAAGGTAAGAAAACGGTTGACCTGGGCCAATGCGGCCTGCTGGGCACAATCACAGGT CCGCCCCAGTGCGATCAGTTCCTGGAGTTCTCAGCGGATCTGATAATTGAGCGGCGAGAG GGGTCAGATGTATGTTACCCAGGTAAATTCGTCAACGAGGAGGCACTGCGGCAGATCCTG CGAGAAAGTGGAGGGATAGAAAAGGAAGCAATGGGTTTTACCTACTCCGGAATCCGAGCC AATGGGGCCACTTCCGCGTGTAGGAGAAGCGGAAGTTCTTTCTACGCTGAAATGAAGTGG CTCCTGAGTAACACAGATAACGCGGCTTTCCCTCAAATGACCAAGTCATACAAGAATACG CGCAAGTCACCAGCCCTCATTGTGTGGGGAATCCATCATTCCGTCTCGACTGCGGAACAG ACAAAACTCTACGGATCCGGAAACAAACTGGTGACCGTAGGTTCCAGTAATTACCAGCAA AGTTTTGTGCCCTCACCCGGAGCCAGGCCTCAGGTCAATGGGTTAAGTGGGCGCATTGAC TTCCACTGGTTGATGCTGAATCCCAACGACACAGTGACTTTCTCTTTCAACGGGGCTTTC ATAGCTCCCGATCGGGCCTCTTTCCTGCGGGGTAAGTCTATGGGTATTCAAAGCGGCGTC CAGGTGGATGCTAATTGTGAAGGGGACTGTTACCACTCGGGAGGCACAATCATTAGTAAC CTGCCTTTCCAGAATATTGACTCGAGGGCAGTAGGCAAGTGTCCCCGCTATGTGAAGCAA AGGTCACTCCTTTTGGCAACCGGGATGAAGAATGTGCCCGAGATACCAAAGGGTAGAGGG CTATTTGGCGCAATTGCAGGATTTATCGAGAATGGTTGGGAGGGCCTGATTGACGGCTGG TACGGGTTTCGGCATCAGAATGCCCAGGGGGAAGGGACTGCCGCAGACTACAAAAGCACA CAGTCGGCTATTGATCAGATAACGGGAAAACTGAACAGGTTGATTGAGAAGACCAACCAA CAATTCGAACTTATAGACAACGAGTTCAACGAGGTCGAGAAGCAAATCGGCAACGTGATC AATTGGACCCGGGACTCGATCACCGAGGTGTGGTCATATAACGCTGAGCTGTTAGTAGCT ATGGAGAATCAGCACACGATCGACCTTGCAGATAGCGAGATGGATAAACTGTATGAACGG GTCAAGCGGCAGCTGAGAGAAAATGCCGAAGAGGACGGTACGGGCTGCTTTGAAATTTTT CATAAGTGCGACGATGACTGCATGGCCAGTATTAGAAACAACACCTACGACCATTCCAAA TATCGGGAAGAAGCGATGCAGAACAGAATTCAGATAGATCCAGTTAAGCTGTCCTCTGGA TATAAGGATGTGATACTGTGGTTTTCTTTTGGCGCCAGTTGCTTTATATTGCTCGCAATT GTGATGGGGCTGGTGTTCATTTGCGTCAAAAACGGGAACATGAGGTGCACCATTTGCATT 638 ATGAATACACAGATTCTGGTATTTGCTCTGATCGCGATTATTCCGACGAATGCAGATAAG ATCTGTTTAGGCCACCACGCTGTTAGCAATGGGACGAAAGTGAATACTCTAACAGAACGT GGGGTGGAAGTCGTCAATGCTACGGAGACTGTCGAGCGCACCAATATTCCAAGGATCTGT TCCAAGGGTAAGAAGACTGTGGACCTCGGGCAATGCGGTCTCCTAGGCACCATTACCGGT CCTCCTCAGTGCGATCAGTTTCTGGAATTCTCTGCAGATCTTATTATAGAGCGGCGCGAG GGCAGTGATGTGTGCTACCCAGGTAAGTTCGTCAATGAAGAGGCTCTGCGTCAAATTTTG AGAGAGTCAGGCGGCATTGATAAGGAGGCCATGGGCTTTACCTACAGCGGAATCCGCACC AACGGAGCAACCAGCGCCTGTCGGAGAAGCGGTAGCAGTTTCTACGCCGAAATGAAATGG CTACTTTCTAATACCGATAATGCTGCGTTTCCACAGATGACAAAGAGTTACAAGAACACC CGTAAGAGTCCTGCCCTCATCGTGTGGGGGATCCATCACAGTGTGTCAACCGCAGAGCAA ACCAAATTGTATGGTTCCGGAAACAAACTGGTTACCGTGGGCTCTAGCAATTACCAGCAG AGTTTCGTTCCGTCCCCCGGCGCTAGACCCCAAGTCAATGGTCAGAGCGGAAGAATCGAT TTCCACTGGCTGATGCTGAATCCCAATGACACTGTGACTTTCTCCTTTAATGGGGCCTTC ATTGCTCCCGACCGCGCTTCATTCTTGCGCGGCAAATCCATGGGAATACAGAGCGGTGTG CAGGTGGATGCCAATTGCGAAGGTGATTGTTATCACAGTGGAGGAACTATTATCTCTAAT CTGCCGTTTCAGAACATTGACAGCAGAGCCGTTGGCAAGTGTCCACGATACGTCAAACAG CGGTCCCTCCTGTTGGCCACAGGCATGAAGAACGTGCCTGAGATCCCTAAGGGGCGCGGA CTGTTTGGAGCCATCGCGGGATTTATTGAGAACGGATGGGAAGGCTTGATAGATGGCTGG TATGGCTTTAGGCACCAGAATGCACAGGGGGAGGGCACCGCCGCTGATTACAAGAGCACG CAGTCTGCGATCGACCAAATAACCGGTAAGTTAAATCGCCTGATCGAGAAAACCAATCAG CAGTTCGAGCTGATCGACAACGAGTTTAATGAAGTCGAAAAACAGATCGGCAACGTGATC AATTGGACCAGGGACAGTATCACAGAGGTATGGAGCTACAATGCCGAGCTGCTGGTGGCC ATGGAGAATCAGCATACAATTGACCTAGCTGATAGTGAGATGGACAAACTGTATGAGAGG GTCAAGAGACAATTGCGGGAAAACGCGGAGGAAGATGGGACAGGCTGCTTCGAGATCTTC CATAAGTGCGACGACGACTGTATGGCCAGTATCAGAAATAACACGTACGACCACTCGAAG TATAGGGAGGAGGCAATGCAGAACAGAATTCAGATCGACCCTGTGAAGCTTAGTAGTGGA TACAAGGACGTGATTCTCTGGTTCTCTTTCGGGGCCTCATGTTTCATTTTGCTCGCTATA GTTATGGGCCTAGTGTTCATCTGCGTGAAGAATGGGAATATGCGGTGCACGATTTGCATC 639 ATGAATACTCAGATCTTAGTGTTCGCATTGATCGCCATCATCCCAACCAACGCCGATAAA ATTTGCCTTGGACATCATGCTGTGAGCAACGGCACAAAGGTCAATACACTTACAGAAAGA GGGGTGGAAGTGGTGAACGCCACAGAAACCGTGGAACGGACGAACATTCCCCGAATTTGT TCTAAGGGAAAGAGAACAGTAGACCTCGGACAGTGTGGCCTCCTGGGCACCATAACCGGC CCTCCACAGTGTGACCAGTTTCTGGAATTCAGCGCGGATCTGATTATTGAGAGGCGGGAG GGCTCCGATGTCTGCTACCCTGGCAAGTTTGTGAACGAGGAGGCCCTGAGGCAGATCCTA CGGGAGTCCGGAGGGATCGATAAAGAGGCAATGGGTTTTACCTACAGCGGCATCCGGACC AATGGAGCCACTTCTGCATGCCGGCGCTCCGGGAGTTCATTTTATGCTGAGATGAAATGG TTACTTTCTAACACCGATAACGCAGCCTTCCCACAGATCACCAAGAGCTATAAAAATACG CGAAAATCTCCAGCCCTCATAGTCTGGGGTATCCATCACTCTGTTAGCACAGCGGAGCAG ACCAAGTTATACGGGTCAGGAAATAAACTTGTGACAGTGGGCTCCTCTAACTATCAGCAG TCTTTTGTGCCCAGCCCTGGGGCCAGGCCCCAAGTCAATGGCCTTTCTGGTAGGATTGAT TTCCACTGGTTGATGTTGAACCCCAATGATACCGTCACATTCAGCTTTAATGGTGCTTTT ATCGCCCCTGACCGAGCTAGTTTCCTAAGAGGAAAATCTATGGGTATCCAGTCTGGCGTT CAGGTGGACGCCAATTGTGAGGGCGACTGTTATCATTCCGGGGGAACCATCATCTCTAAC CTTCCCTTCCAAAATATCGACTCCAGGGCAGTTGGCAAATGTCCACGGTATGTGAAGCAG AGATCACTCCTGTTAGCGACTGGGATGAAAAACGTGCCAGAAATCCCTAAAGGTCGTGGA TTGTTCGGAGCGATCGCGGGATTTATCGAAAACGGGTGGGAGGGTCTTATAGACGGCTGG TATGGGTTTAGACACCAGAACGCACAGGGTGAGGGCACCGCGGCAGACTACAAATCTACA CAATCTGCAATAGATCAGATCACCGGCAAGCTGAACCGACTTATTGAAAAGACCAATCAG CAGTTTGAGTTAATCGATAACGAATTCAACGAGGTGGAGAAGCAAATAGGGAATGTTATT AACTGGACACGGGACTCAATCACAGAAGTATGGTCGTATAATGCAGAGCTGCTAGTCGCA ATGGAGAATCAGCATACGATTGACCTCGCCGACAGTGAGATGGACAAGTTGTATGAAAGG GTCAAAAGACAGCTCCGGGAAAATGCCGAGGAAGACGGCACAGGCTGTTTTGAAATATTC CATAAGTGCGACGATGACTGCATGGCAAGTATTAGGAACAACACGTATGACCATTCAAAG TACAGGGAGGAGGCCATGCAGAACCGCATCCAGATTGATCCAGTTAAGCTTAGCAGTGGC TATAAGGATGTCATCCTGTGGTTTAGTTTTGGCGCCTCCTGTTTTATCCTGCTGGCCATC GTTATGGGGCTTGTGTTCATATGCGTGAAGAATGGCAATATGCGCTGCACCATTTGTATT 640 ATGAATACACAAATTCTGGTATTCGCCCTCATAGCTATAATTCCCACCAACGCCGATAAG ATTTGTTTAGGTCACCACGCCGTGTCAAACGGGACAAAGGTTAATACACTTACAGAGCGG GGCGTGGAAGTCGTGAACGCTACTGAGACAGTCGAAAGGACTAACATCCCCAGAATTTGT AGCAAAGGAAAAAAGACCGTGGATTTGGGGCAGTGTGGCTTACTAGGGACAATCACCGGT CCACCCCAGTGTGACCAGTTCCTCGAGTTCTCAGCGGACCTAATTATCGAGCGTCGAGAG GGCAGCGATGTGTGCTATCCCGGGAAATTCGTGAATGAGGAGGCCTTACGGCAGATCTTG CGTGAAAGTGGGGGCATAGATAAAGAGGCGATGGGGTTCACGTATTCTGGCATTCGCACC AACGGAGCTACCTCAGCCTGTCGTCGTTCAGGATCCAGCTTCTACGCAGAAATGAAGTGG TTACTCTCTAACACAGATAACGCAGCCTTCCCGCAAATGACGAAGAGCTACAAAAACACT CGCAAATCCCCCGCCCTCATCGTCTGGGGTATTCACCACAGCGTTAGCACCGCTGAACAG ACTAAATTATACGGCAGCGGAAATAAGCTTGTCACCGTCGGGAGCTCCAACTATCAGCAG AGCTTTGTCCCATCTCCTGGGGCCCGGCCCCAGGTGAACGGACAGTCCGGGCGCATTGAT TTCCACTGGTTGATGCTGAACCCAAACGACACTGTTACGTTCAGCTTTAACGGCGCCTTC ATTGCACCTGACCGAGCTAGCTTTTTGCGGGGCAAATCGATGGGAATACAGTCAGGGGTC CAGGTAGACGCCAACTGCGAAGGCGATTGCTACCATTCCGGCGGGACAATCATCTCCAAC CTGCCCTTCCAGAACATTGACAGCCGGGCAGTCGGGAAGTGTCCCAGATATGTGAAACAA CGCTCTCTGCTGCTTGCGACCGGCATGAAAAACGTTCCAGAAATCCCGAAGGGGCGAGGT TTGTTTGGCGCTATAGCTGGGTTCATTGAGAACGGCTGGGAAGGCCTCATCGACGGCTGG TATGGATTTAGGCATCAAAATGCACAGGGCGAAGGTACCGCTGCCGACTATAAGTCAACT CAGAGCGCAATAGACCAAATTACCGGAAAGCTCAATCGCCTGATTGAGAAAACCAATCAG CAGTTTGAACTGATAGACAACGAATTTAATGAAGTGGAGAAGCAGATCGGGAATGTGATC AACTGGACTCGTGACAGTATTACTGAGGTATGGAGTTATAACGCTGAACTTCTGGTGGCT ATGGAGAACCAACACACTATTGATCTCGCCGACTCCGAGATGGATAAACTCTACGAAAGA GTTAAAAGACAGCTTAGGGAAAACGCCGAGGAGGATGGTACTGGATGTTTCGAGATCTTT CATAAATGCGATGACGACTGCATGGCTAGCATCCGGAATAACACCTACGATCATTCTAAG TATCGTGAAGAAGCCATGCAAAATCGTATTCAGATTGATCCGGTAAAATTGAGCTCAGGC TATAAGGACGTCATACTGTGGTTCTCCTTCGGCGCTTCCTGCTTTATCTTATTAGCAATT GTGATGGGATTAGTTTTCATCTGCGTGAAAAACGGAAACATGCGCTGTACCATTTGCATA 641 ATGAACACTCAAATTTTAGTGTTCGCCTTGATAGCAATCATCCCCACAAATGCGGATAAA ATCTGTCTCGGCCATCATGCCGTGTCTAATGGTACCAAAGTAAATACCCTTACCGAGCGT GGGGTTGAGGTCGTTAATGCCACCGAGACTGTGGAGAGAACCAATATCCCCCGCATCTGT TCCAAGGGAAAAAAGACCGTTGACCTCGGTCAGTGTGGTCTGCTTGGTACAATAACCGGA CCGCCCCAGTGCGACCAATTCCTGGAATTCAGTGCGGATCTCATAATCGAAAGGCGAGAA GGCTCCGATGTTTGTTACCCCGGAAAGTTCGTCAACGAGGAGGCCCTGCGACAGATATTG CGGGAAAGCGGAGGCATCGATAAGGAGGCTATGGGCTTCACATATAGTGGAATCCGCACG AATGGGGCCACCTCAGCCTGTCGGCGCAGCGGGTCTAGTTTTTATGCTGAAATGAAGTGG CTTCTTTCGAATACTGACAATGCTGCCTTCCCCCAGATGACCAAGAGTTATAAAAATACC AGAAAGAGCCCTGCCCTGATAGTCTGGGGAATCCATCACAGCGTAAGCACTGCCGAACAG ACTAAGCTCTATGGCAGCGGGAATAAGCTCGTGACCGTGGGCAGTTCCAATTACCAGCAG AGCTTTGTGCCATCCCCGGGGGCCCGTCCACAGGTTAACGGGCAATCTGGCCGAATTGAT TTTCATTGGCTGATGCTGAATCCAAACGATACTGTGACTTTCTCTTTTAACGGAGCCTTC ATTGCACCCGATCGGGCAAGCTTCCTGCGGGGAAAATCTATGGGAATTCAGAGTGGGGTG CAGGTGGACGCAAACTGTGAAGGCGATTGCTACCACTCTGGCGGGACAATCATTAGCAAT CTGCCTTTCCAGAACATAGACAGCCGCGCAGTTGGAAAATGCCCGCGTTATGTCAAGCAA AGGAGTTTACTGCTCGCTACAGGCATGAAGAATGTTCCGGAGATCCCGAAGGGAAGAGGT TTGTTCGGCGCCATAGCAGGATTCATTGAAAATGGCTGGGAAGGGTTAATCGACGGGTGG TATGGTTTTCGACACCAGAACGCACAAGGGGAGGGGACAGCAGCAGATTACAAGAGCACA CAGTCAGCAATTGACCAGATTACTGGAAAGCTAAACCGGCTCATCGAGAAGACCAACCAG CAGTTCGAATTGATTGACAACGAATTTAATGAGGTGGAAAAACAGATCGGTAACGTCATA AACTGGACTAGAGATTCCATTACTGAGGTCTGGTCATATAATGCCGAACTGCTCGTGGCG ATGGAGAATCAGCATACCATAGATCTCGCCGACTCCGAGATGGACAAACTTTATGAACGG GTGAAGCGCCAGCTGCGGGAAAATGCCGAAGAGGACGGTACAGGGTGTTTCGAGATTTTC CATAAATGTGATGACGACTGCATGGCAAGCATACGCAATAACACATATGATCACTCTAAG TATAGGGAAGAGGCCATGCAGAACCGAATTCAAATCGACCCAGTAAAGCTTTCTAGCGGC TATAAAGATGTGATTCTGTGGTTTAGCTTCGGGGCCTCTTGTTTTATCCTGTTAGCCATC GTCATGGGGCTAGTTTTCATCTGCGTGAAAAATGGCAACATGCGTTGCACTATATGCATC 642 ATGAATACGCAGATCCTCGTGTTCGCACTGATAGCGATCATCCCGACAAATGCTGACAAA ATCTGTTTGGGCCATCATGCCGTTAGCAATGGTACCAAAGTGAACACTCTCACTGAGCGC GGCGTGGAAGTGGTGAACGCCACTGAAACAGTAGAAAGAACAAACATTCCCAGAATCTGC AGTAAGGGTAAGAAAACTGTCGACTTGGGCCAGTGTGGCCTATTAGGAACAATCACCGGA CCTCCCCAATGCGATCAGTTCCTAGAATTTAGCGCTGATCTGATAATTGAAAGAAGAGAA GGTTCGGATGTCTGTTACCCGGGTAAATTCGTGAACGAAGAAGCCTTAAGACAGATTCTC AGAGAAAGTGGCGGAATTGATAAAGAAGCCATGGGGTTCACTTATTCTGGCATACGGACA AATGGGGCCACTAGCGCATGTAGACGATCAGGCAGCTCTTTCTACGCCGAGATGAAGTGG CTGTTATCCAACACAGACAATGCAGCCTTTCCTCAGATGACCAAATCCTACAAAAATACA AGGAAGAGCCCCGCACTAATCGTATGGGGCATCCATCACTCTGTGTCGACGGCAGAACAA ACCAAGCTCTATGGTAGTGGGAACAAGTTGGTGACGGTGGGGTCCTCTAATTACCAGCAG TCGTTCGTGCCCTCTCCAGGTGCCCGGCCCCAGGTGAATGGTCAGTCCGGCCGAATCGAC TTTCACTGGCTTATGCTGAATCCCAATGATACCGTAACATTTAGCTTTAATGGAGCTTTC ATTGCTCCTGACCGTGCCAGCTTCTTGAGAGGAAAATCTATGGGCATACAGTCTGGTGTC CAGGTGGATGCTAACTGCGAAGGTGACTGTTACCACTCAGGAGGTACTATAATTAGCAAT CTCCCCTTCCAGAACATCGACAGCCGCGCTGTAGGAAAGTGCCCTCGCTACGTGAAGCAA CGATCATTACTGCTGGCCACTGGCATGAAGAACGTACCCGAGATCCCAAAGGGAAGGGGT TTGTTTGGCGCCATTGCGGGCTTTATTGAGAACGGATGGGAGGGTCTGATCGATGGATGG TATGGATTCCGTCATCAGAATGCCCAGGGCGAGGGGACCGCTGCTGATTACAAATCCACA CAATCTGCAATAGATCAAATCACAGGAAAACTGAACCGGCTTATTGAAAAAACCAATCAG CAGTTCGAGTTGATCGACAATGAGTTCAATGAAGTGGAAAAGCAGATCGGCAACGTCATC AACTGGACTCGGGACTCTATCACAGAGGTCTGGTCCTACAATGCAGAGTTACTAGTTGCC ATGGAGAACCAGCACACGATTGATTTGGCCGATAGCGAGATGGATAAACTCTACGAGCGT GTGAAGAGGCAGCTGCGCGAAAATGCCGAAGAGGATGGAACAGGTTGCTTCGAGATCTTC CACAAATGCGATGACGACTGCATGGCCTCCATCAGGAATAATACTTATGATCACAGCAAG TACCGGGAGGAAGCCATGCAAAACAGAATTCAGATTGATCCCGTAAAGTTAAGCTCCGGC TACAAAGATGTGATTCTGTGGTTCTCTTTCGGAGCTTCATGCTTCATCCTCCTCGCTATA GTGATGGGTCTCGTATTCATTTGCGTTAAGAACGGCAATATGAGATGCACAATCTGTATT 643 ATGAATACTCAAATCCTGGTGTTCGCACTCATTGCCATCATACCAACCAACGCAGACAAG ATATGCTTGGGCCATCACGCCGTGTCTAATGGTACGAAAGTGAATACTCTGACTGAGCGC GGGGTCGAAGTAGTAAACGCGACTGAAACAGTGGAACGAACTAATATTCCCAGAATTTGC AGTAAAGGGAAAAAGACCGTCGATCTCGGCCAATGCGGACTGCTGGGGACAATCACAGGG CCACCGCAATGCGATCAGTTCCTGGAGTTTAGCGCGGATCTCATCATCGAGCGAAGAGAA GGGTCCGACGTCTGTTACCCGGGTAAATTTGTGAATGAAGAGGCCCTGCGTCAGATTCTG CGGGAAAGCGGCGGAATTGACAAGGAGGCAATGGGGTTCACGTACAGTGGTATCAGAACC AACGGAGCTACAAGCGCATGCAGACGGTCCGGGTCCTCGTTTTACGCGGAGATGAAGTGG CTGTTATCCAACACTGACAACGCTGCTTTCCCACAGATGACCAAAAGCTATAAGAACACA AGAAAAAGTCCAGCCCTGATTGTGTGGGGGATCCACCATTCGGTATCAACTGCTGAGCAA ACAAAGTTATATGGAAGTGGAAACAAGCTTGTCACCGTAGGTTCATCCAACTATCAACAG AGTTTCGTGCCCTCCCCCGGAGCCCGCCCCCAGGTGAATGGACAGTCGGGAAGAATAGAC TTTCATTGGTTGATGCTGAATCCCAATGACACCGTGACCTTCAGCTTTAATGGGGCCTTC ATTGCCCCGGACAGGGCTAGCTTTCTCCGAGGAAAGAGCATGGGCATTCAATCTGGAGTT CAAGTGGATGCCAACTGTGAGGGCGATTGCTACCATAGCGGAGGGACAATCATCAGCAAC CTCCCCTTCCAAAACATTGATAGTCGTGCTGTAGGAAAATGCCCTCGGTACGTTAAACAA AGATCGCTGCTACTGGCTACAGGAATGAAGAACGTGCCCGAGATCCCAAAAGGACGAGGC CTATTTGGGGCCATCGCGGGTTTTATCGAAAATGGATGGGAGGGCCTCATCGACGGGTGG TATGGCTTTCGTCATCAGAATGCTCAAGGCGAAGGAACAGCCGCTGATTACAAATCAACC CAATCTGCCATCGACCAGATCACCGGAAAGCTCAACCGCCTGATTGAAAAGACTAATCAG CAGTTCGAGCTGATCGACAATGAGTTCAATGAAGTGGAAAAGCAGATTGGTAACGTGATT AACTGGACTAGAGATTCCATTACCGAAGTGTGGTCTTATAACGCCGAGCTACTGGTCGCC ATGGAGAACCAGCATACCATTGATTTAGCTGATTCTGAGATGGACAAGCTGTACGAAAGG GTGAAACGGCAGCTCCGAGAAAATGCCGAAGAAGACGGAACCGGGTGTTTCGAGATCTTC CACAAGTGCGACGACGATTGCATGGCTAGCATTAGAAACAACACTTATGACCACAGCAAG TATCGCGAAGAGGCGATGCAGAATCGAATCCAGATCGATCCTGTCAAGCTGAGCAGCGGG TACAAGGACGTGATCTTATGGTTTTCCTTCGGGGCTAGCTGTTTTATCCTGCTGGCTATC GTGATGGGTCTGGTTTTTATATGTGTTAAAAACGGCAACATGCGGTGCACAATCTGCATT 644 ATGAATACCCAGATTTTAGTGTTTGCACTTATCGCTATCATACCAACTAATGCTGACAAG ATCTGCCTGGGCCACCATGCAGTGAGCAACGGGACCAAAGTGAACACCCTAACCGAGCGG GGCGTGGAGGTGGTAAATGCCACTGAAACCGTCGAAAGGACGAACATTCCGCGGATTTGC AGTAAAGGCAAACGAACCGTGGACCTGGGCCAGTGTGGCCTCCTGGGGACCATCACGGGA CCACCCCAATGTGACCAGTTCCTGGAGTTCTCCGCTGACCTTATCATCGAAAGGCGAGAA GGGTCTGATGTCTGTTACCCTGGAAAATTCGTAAACGAGGAGGCTCTCCGACAAATTCTG CGGGAATCCGGCGGCATCGACAAGGAGGCGATGGGTTTTACCTATTCCGGGATACGCACT AACGGAGCTACATCAGCATGTAGGCGCTCTGGGTCTAGTTTCTATGCCGAAATGAAATGG TTGCTGTCAAACACTGACAACGCTGCTTTCCCTCAGATGACTAAGTCCTATAAGAATACC CGGAAGTCCCCAGCACTAATAGTCTGGGGGATTCACCACTCCGTATCTACTGCGGAGCAG ACGAAACTTTACGGGAGCGGGAACAAACTGGTCACTGTTGGGTCATCAAATTATCAGCAA TCATTCGTACCCTCTCCCGGCGCTCGGCCCCAGGTCAATGGCCTGTCCGGCAGAATTGAC TTCCACTGGCTTATGCTAAATCCTAACGACACCGTGACCTTCTCCTTCAACGGCGCCTTC ATCGCGCCTGACCGAGCTAGCTTTCTGCGTGGGAAAAGTATGGGAATTCAGAGCGGTGTG CAGGTGGATGCAAATTGTGAAGGCGACTGCTATCATAGCGGGGGTACCATTATCTCTAAT CTGCCTTTCCAGAACATCGACAGTAGAGCCGTGGGCAAATGCCCCAGATATGTGAAACAA CGTAGCCTTCTGCTGGCAACAGGAATGAAAAATGTGCCCGAGATTCCCAAAGGGCGTGGG CTGTTTGGGGCCATCGCCGGCTTCATCGAAAACGGTTGGGAGGGATTAATCGACGGGTGG TATGGCTTCAGGCACCAAAACGCTCAAGGGGAGGGCACGGCGGCGGATTACAAATCTACC CAGTCCGCCATTGATCAAATTACTGGCAAATTAAACAGAATCATCGAAAAGACTAACCAG CAGTTCGAACTGATTGATAATGAGTTCAACGAGGTTGAGAAGCAAATCGGTAACGTTATC AACTGGACGCGTGACAGTATCACCGAGGTCTGGTCATATAATGCTGAGCTGCTCGTGGCT ATGGAAAACCAGCACACTATCGATCTGGCGGACTCCGAGATGGACAAGTTGTATGAACGG GTGAAAAGACAGCTTCGGGAGAACGCCGAGGAGGACGGGACCGGATGCTTCGAGATCTTT CACAAGTGCGATGATGATTGCATGGCTTCAATTCGCAATAATACATATGACCATTCTAAG TACAGGGAGGAGGCTATGCAGAACCGGATCCAGATAGATCCCGTCAAACTTAGTAGCGGG TACAAGGATGTCATCCTGTGGTTTTCCTTCGGGGCCTCATGCTTTATTCTTCTGGCCATC GTGATGGGACTCGTGTTCATCTGCGTTAAGAATGGCAACATGCGATGTACAATCTGCATC 645 ATGAACACCCAGATTCTCGTGTTCGCTTTGATCGCGATTATACCTACTAACGCAGATAAA ATATGTCTGGGTCATCACGCTGTCAGTAACGGGACAAAGGTGAACACGTTGACCGAGAGG GGCGTCGAGGTGGTTAACGCCACTGAAACAGTGGAACGGACCAATATACCAAGGATCTGT AGCAAGGGTAAGAAGACTGTCGACCTCGGTCAGTGTGGGTTGCTTGGGACCATCACCGGG CCTCCACAGTGTGATCAGTTTCTGGAGTTCTCGGCTGACCTGATAATCGAGAGACGGGAG GGCAGTGACGTGTGCTACCCAGGGAAGTTTGTGAACGAAGAAGCATTGCGACAGATTCTT CGGGAATCAGGTGGAATCGACAAGGAGGCCATGGGATTTACATACTCTGGGATCAGGACC AACGGTGCTACCTCCGCTTGTAGGAGAAGTGGATCAAGCTTTTATGCTGAAATGAAATGG CTTCTGTCCAATACGGACAACGCAGCTTTCCCTCAGATGACAAAGTCCTACAAAAACACA AGAAAGTCACCCGCTCTGATTGTTTGGGGAATCCACCACTCAGTGTCCACGGCGGAGCAG ACGAAACTCTATGGCTCTGGGAATAAGCTGGTGACAGTCGGGAGCTCAAATTATCAGCAA TCCTTCGTTCCATCCCCCGGCGCCCGACCTCAGGTCAACGGCCAATCGGGCAGGATTGAC TTCCATTGGCTAATGCTCAATCCCAATGACACCGTCACATTCTCTTTTAATGGTGCCTTC ATCGCCCCAGATCGAGCCTCTTTTCTCAGAGGTAAGTCGATGGGAATACAGTCAGGGGTT CAGGTGGACGCTAATTGCGAAGGGGACTGCTATCATTCTGGGGGCACAATTATTTCAAAT CTGCCATTCCAGAACATTGACTCTCGAGCCGTCGGAAAATGCCCTCGATATGTAAAGCAG CGAAGTCTGCTGCTGGCAACCGGCATGAAAAACGTACCCGAGATCCCAAAGGGCAGAGGG CTTTTCGGTGCGATCGCCGGGTTTATCGAAAATGGCTGGGAGGGCCTGATCGATGGGTGG TACGGTTTTCGGCACCAGAACGCTCAGGGTGAGGGCACTGCAGCGGATTATAAGAGTACC CAGTCAGCCATTGACCAGATCACAGGTAAGTTGAACCGCCTCATTGAAAAGACCAACCAG CAGTTTGAGCTGATCGATAATGAGTTTAATGAGGTGGAGAAGCAGATCGGGAATGTTATT AATTGGACGCGCGATTCAATCACAGAGGTATGGTCATACAACGCTGAGCTGCTGGTGGCA ATGGAGAATCAACACACGATCGACCTCGCTGACTCAGAAATGGATAAACTGTACGAAAGG GTCAAAAGGCAGCTGCGCGAGAACGCCGAAGAAGACGGAACTGGTTGTTTCGAAATTTTC CACAAGTGTGACGACGACTGTATGGCATCCATCAGAAACAACACATACGACCATAGCAAA TACCGGGAGGAGGCAATGCAGAATCGAATCCAGATTGATCCCGTGAAGTTGTCTAGCGGA TACAAAGATGTGATCTTATGGTTTTCATTCGGGGCTAGCTGTTTCATCCTCCTGGCCATA GTTATGGGGCTCGTTTTCATCTGCGTAAAGAATGGGAATATGAGATGTACTATCTGCATT 646 ATGAATACGCAGATTCTGGTGTTCGCTCTCATCGCTATTATTCCTACCAATGCCGATAAG ATCTGTCTGGGGCACCACGCCGTCAGCAACGGCACTAAAGTGAACACCTTGACAGAAAGG GGGGTGGAAGTGGTGAACGCAACGGAAACAGTGGAGAGGACAAACATACCGCGGATTTGC TCGAAAGGAAAACGGACTGTAGACCTGGGCCAATGCGGCCTGCTCGGAACCATCACCGGG CCACCCCAATGTGACCAGTTCCTAGAATTTTCCGCCGACCTTATAATTGAGCGGAGGGAG GGATCCGATGTGTGTTATCCTGGCAAGTTCGTGAACGAGGAGGCCCTGCGGCAGATATTG CGTGAATCTGGGGGCATCGACAAGGAGGCGATGGGATTCACATACTCCGGCATCCGCACC AACGGCGCGACCAGCGCATGCCGTCGCTCCGGGTCCTCATTCTACGCTGAAATGAAATGG CTCCTCTCAAATACTGATAATGCTGCTTTTCCTCAAATGACCAAAAGTTACAAAAACACC AGGAAAAGCCCAGCTCTGATTGTCTGGGGCATTCACCATTCCGTATCTACGGCAGAACAG ACTAAACTATATGGCAGTGGCAGCAAGCTCGTGACCGTCGGCTCCTCCAACTATCAGCAA TCTTTCGTTCCATCACCAGGCGCCCGGCCCCAGGTCAATGGGCTCTCCGGCCGTATCGAT TTCCACTGGCTGATGCTCAATCCTAACGACACCGTTACCTTTTCTTTTAACGGCGCCTTT ATTGCTCCAGACAGAGCGTCTTTCCTGCGGGGTAAAAGCATGGGCATTCAGTCTGGTGTC CAAGTGGACGCAAACTGTGAAGGGGATTGCTATCATAGTGGCGGCACTATCATTAGTAAC CTGCCTTTCCAGAACATTGATTCGCGGGCAGTTGGCAAATGCCCCAGGTATGTCAAACAG AGATCACTCTTGTTAGCTACCGGAATGAAGAACGTACCGGAGATTCCTAAGGGTAGGGGA CTGTTCGGGGCTATTGCCGGGTTCATCGAGAATGGGTGGGAAGGTCTCATCGACGGGTGG TATGGCTTTCGTCATCAGAACGCCCAGGGCGAAGGTACAGCAGCCGATTATAAGTCTACC CAGTCCGCTATCGACCAAATAACCGGGAAGTTGAACCGGTTAATCGAGAAAACCAACCAA CAGTTCGAATTGATCGACAATGAATTTAATGAGGTGGAAAAACAAATAGGGAACGTGATA AACTGGACAAGGGACTCCATTACAGAAGTCTGGAGCTATAACGCCGAACTGCTGGTAGCT ATGGAGAATCAGCATACCATTGACCTGGCAGACAGTGAGATGGACAAACTTTACGAACGG GTTAAAAGACAGTTGCGAGAGAATGCCGAAGAAGATGGAACTGGCTGCTTTGAGATTTTT CACAAATGCGATGATGACTGTATGGCCAGCATTAGAAACAACACATACGACCACAGTAAG TACAGGGAAGAAGCCATGCAAAACCGGATCCAGATTGACCCCGTCAAGCTGAGCTCGGGT TATAAGGATGTAATCTTATGGTTCAGTTTTGGCGCCTCCTGCTTCATTCTTCTAGCAATC GTGATGGGATTGGTCTTCATTTGCGTGAAAAATGGCAATATGAGGTGCACCATCTGCATT 647 ATGAATACACAGATCCTAGTCTTCGCCTTAATTGCAATAATACCTACCAACGCAGACAAA ATTTGTCTTGGGCACCACGCCGTGTCCAACGGGACCAAAGTTAATACCCTCACCGAACGT GGGGTGGAGGTGGTAAACGCTACGGAGACAGTAGAAAGGACCAACATACCTCGCATCTGT TCCAAAGGGAAAAGAACCGTCGACCTGGGGCAGTGCGGGCTGCTAGGAACTATTACTGGC CCACCACAGTGCGATCAGTTTCTGGAATTTAGTGCTGATCTGATCATCGAAAGGCGTGAG GGTAGCGATGTCTGTTATCCCGGGAAGTTCGTGAATGAAGAGGCGCTGAGACAAATTCTG AGAGAAAGCGGGGGGATCGATAAGGAAGCAATGGGGTTTACTTATTCTGGCATTAGAACC AATGGGGCCACATCCGCCTGCCGCAGGTCTGGAAGCTCCTTTTATGCTGAAATGAAATGG CTGCTGAGTAATACTGACAACGCCGCTTTTCCTCAGATGACAAAATCTTATAAAAACACG AGAAAATCTCCTGCCCTGATTGTGTGGGGCATTCACCATTCGGTTTCAACAGCGGAGCAA ACTAAACTATATGGAAGCGGCAGCAAGCTGGTCACAGTGGGAAGCTCTAACTACCAACAG TCTTTTGTTCCCAGTCCCGGCGCCCGACCTCAGGTCAACGGACTGAGTGGCAGAATTGAT TTCCACTGGCTGATGCTTAATCCGAACGATACCGTCACCTTTTCTTTCAATGGTGCTTTT ATTGCCCCTGACAGGGCAAGCTTCTTGCGCGGGAAGTCTATGGGAATCCAATCCGGCGTA CAAGTGGACGCAAACTGTGAAGGGGACTGTTATCACTCCGGAGGCACAATTATTAGTAAC TTGCCTTTCCAGAATATCGATTCCAGAGCCGTGGGTAAATGCCCTCGATACGTAAAACAG CGCTCTCTGCTTCTGGCTACCGGAATGAAGAATGTGCCTGAGATCCCTAAGGGCAGAGGC CTGTTCGGGGCCATCGCTGGTTTTATTGAGAATGGGTGGGAAGGCTTAATAGACGGGTGG TACGGTTTTCGTCACCAAAATGCACAGGGCGAAGGCACAGCAGCCGACTACAAAAGTACG CAAAGCGCCATAGATCAGATAACAGGAAAACTTAATCGCCTGATCGAAAAAACGAACCAA CAGTTCGAACTGATTGACAATGAATTTAACGAAGTCGAAAAGCAGATAGGCAATGTCATC AATTGGACGAGAGACAGTATTACAGAAGTTTGGAGCTATAATGCAGAGCTGTTAGTGGCG ATGGAAAATCAGCACACCATTGATTTGGCGGACAGCGAAATGGACAAGCTGTACGAACGA GTGAAGCGACAGCTACGCGAGAATGCAGAAGAAGATGGGACTGGCTGCTTCGAAATCTTT CACAAGTGCGACGACGATTGCATGGCCAGCATTCGCAATAACACATACGATCACTCCAAG TATCGAGAGGAGGCGATGCAAAACCGAATCCAAATTGACCCTGTGAAATTATCTAGTGGG TATAAAGACGTGATACTGTGGTTTTCATTCGGAGCTTCATGTTTCATTCTGTTGGCAATT GTCATGGGACTGGTGTTTATATGTGTAAAAAGCAGAAATATGCGATGCACCATTTGCATC 648 ATGAATACCCAGATCCTGGTATTCGCATTAATTGCTATCATTCCTACAAATGCTGACAAA ATCTGTCTCGGCCATCACGCCGTGAGTAATGGAACTAAAGTGAATACTCTCACTGAGCGC GGGGTAGAGGTAGTGAATGCCACTGAGACCGTCGAGCGAACTAACATCCCCCGCATCTGT AGCAAAGGCAAGAAGACGGTGGACTTAGGACAGTGTGGCCTCCTGGGGACCATCACAGGA CCTCCTCAGTGCGACCAGTTTCTGGAATTTAGTGCTGACCTTATCATTGAACGGCGCGAG GGCAGCGATGTCTGCTACCCTGGCAAGTTTGTCAATGAGGAAGCCTTACGACAGATCCTC AGAGAATCAGGGGGGATTGACAAGGAGGCAATGGGGTTCACCTATAGCGGAATCCGGACT AATGGCGCAACAAGTGCATGTAGACGGAGTGGGAGTAGTTTTTACGCCGAAATGAAGTGG CTGTTAAGCAACACGGACAACGCTGCTTTTCCACAGATGACTAAGTCTTACAAAAACACC AGGAAGTCACCTGCTCTGATCGTGTGGGGAATTCACCATAGCGTGAGCACAGCTGAGCAG ACCAAGCTTTACGGAAGTGGCAACAAACTCGTGACAGTGGGCAGCTCCAACTACCAGCAG TCTTTCGTGCCCTCCCCCGGCGCAAGACCTCAGGTCAACGGGCAGTCGGGGCGTATTGAC TTCCACTGGCTCATGCTGAACCCCAATGATACTGTGACCTTTTCGTTCAATGGGGCGTTT ATCGCCCCTGATCGGGCAAGCTTCCTGAGGGGTAAATCAATGGGAATACAGTCCGGCGTC CAGGTGGATGCCAACTGTGAAGGCGACTGCTATCATTCCGGGGGTACCATTATCAGCAAC CTTCCCTTTCAGAACATTGATTCTCGGGCTGTGGGAAAATGTCCCAGGTACGTCAAGCAG CGGTCACTCCTGCTGGCAACTGGGATGAAGAACGTCCCTGAAATCCCGAAAGGGCGTGGG CTGTTTGGTGCTATCGCTGGATTCATCGAAAACGGCTGGGAAGGGCTTATTGATGGTTGG TACGGGTTTCGCCACCAGAACGCGCAGGGCGAGGGCACCGCTGCAGACTATAAATCTACT CAGTCTGCAATTGACCAGATCACCGGCAAACTGAACCGCCTGATTGAGAAGACCAACCAA CAGTTTGAGCTCATAGATAACGAATTTAACGAGGTGGAAAAGCAAATCGGAAACGTTATC AACTGGACTAGGGACTCTATCACTGAAGTGTGGTCCTACAATGCAGAGCTGCTCGTTGCC ATGGAAAACCAGCACACCATTGACCTAGCTGACTCCGAGATGGATAAACTGTATGAGCGG GTAAAACGGCAGCTGAGAGAGAACGCCGAAGAGGACGGGACAGGATGTTTTGAGATATTT CACAAATGCGACGACGACTGTATGGCAAGCATCCGGAACAACACCTACGATCATTCTAAA TATCGGGAGGAAGCCATGCAGAATCGCATTCAGATTGATCCCGTCAAACTGAGTTCTGGC TATAAGGACGTAATTCTGTGGTTCTCCTTCGGAGCTAGTTGCTTCATTCTGCTTGCAATA GTAATGGGACTCGTTTTTATTTGTGTCAAGAACGGCAACATGAGGTGTACCATTTGCATA 649 ATGAATACACAGATTCTGGTCTTTGCTCTCATCGCTATAATCCCGACCAACGCTGACAAA ATCTGTCTGGGTCACCACGCCGTATCTAATGGAACTAAGGTGAATACATTGACCGAGCGC GGCGTTGAGGTCGTTAATGCTACAGAAACTGTTGAGCGGACAAATATCCCCCGGATATGC TCAAAGGGAAAAAAGACTGTCGACTTAGGACAATGCGGGTTACTAGGCACAATAACAGGG CCGCCCCAGTGCGACCAGTTTCTCGAGTTCAGTGCCGATCTGATTATCGAACGCCGGGAG GGAAGCGACGTCTGTTATCCCGGCAAATTCGTGAATGAAGAGGCCCTCCGCCAGATCCTG AGAGAATCCGGAGGCATCGACAAGGAGGCCATGGGATTCACTTACTCTGGAATCAGGACC AACGGGGCTACCTCCGCGTGCCGACGGTCCGGGTCCTCTTTCTACGCAGAGATGAAGTGG CTACTATCTAATACCGATAACGCAGCTTTCCCCCAAATGACAAAATCATATAAGAATACA AGGAAATCTCCGGCATTGATCGTCTGGGGCATTCATCACTCTGTCAGTACCGCTGAACAA ACAAAGCTGTATGGCAGCGGGAACAAGCTGGTTACAGTGGGGTCTAGTAACTATCAACAG TCCTTCGTGCCATCTCCGGGAGCGCGGCCACAGGTGAATGGGCAGTCTGGCCGGATTGAC TTTCACTGGTTAATGTTAAATCCAAACGACACGGTGACTTTTTCATTTAACGGTGCCTTT ATTGCTCCTGACAGAGCCTCATTTCTCAGAGGCAAATCAATGGGTATCCAATCAGGCGTG CAGGTGGACGCTAACTGCGAGGGCGATTGCTACCACTCTGGGGGCACAATCATATCCAAC CTGCCCTTCCAGAATATTGACTCAAGAGCCGTCGGGAAATGTCCACGGTACGTGAAACAG AGGAGTCTACTGCTAGCTACAGGAATGAAGAATGTGCCCGAGATTCCGAAAGGGAGAGGG TTGTTTGGAGCCATCGCAGGATTCATTGAAAATGGATGGGAAGGTCTCATAGATGGTTGG TATGGCTTTCGACACCAAAACGCGCAGGGCGAGGGGACTGCAGCTGACTACAAAAGTACG CAATCTGCCATTGATCAGATTACAGGAAAGCTCAACCGACTGATCGAAAAAACAAATCAG CAGTTTGAGCTCATAGACAATGAGTTCAATGAAGTGGAAAAGCAGATCGGCAACGTTATC AACTGGACGCGCGACTCAATCACAGAAGTGTGGTCTTACAATGCAGAATTGCTTGTCGCC ATGGAGAATCAGCACACTATCGACCTGGCCGACAGCGAAATGGATAAGCTCTACGAGAGG GTCAAGCGCCAACTTCGAGAGAATGCTGAGGAGGACGGAACCGGTTGCTTTGAGATATTT CACAAGTGTGATGACGATTGCATGGCATCAATCAGAAATAATACTTACGACCATTCGAAA TACAGGGAAGAGGCAATGCAGAACAGAATTCAGATCGACCCTGTGAAGCTTTCTAGTGGG TATAAAGACGTGATCCTCTGGTTCAGTTTTGGAGCATCTTGTTTCATTCTGCTAGCCATT GTTATGGGACTTGTCTTCATTTGCGTGAAGAACGGGAATATGCGTTGTACGATCTGCATT 650 ATGAACACTCAGATACTCGTCTTCGCCCTCATAGCCATCATTCCCACGAATGCCGACAAA ATCTGTCTGGGTCACCACGCGGTAAGTAACGGGACTAAGGTCAACACACTGACAGAAAGA GGCGTCGAAGTCGTGAACGCCACAGAGACGGTGGAGAGGACAAACATACCCAGAATTTGC TCGAAGGGCAAGAAGACCGTAGATCTGGGCCAGTGCGGGCTGTTGGGCACCATCACAGGC CCCCCCCAGTGCGATCAGTTCCTGGAATTCTCTGCCGACCTTATCATTGAAAGGAGAGAG GGGAGCGATGTTTGTTACCCCGGGAAGTTCGTTAACGAGGAGGCCCTTAGACAGATCCTT CGGGAATCCGGTGGGATTGACAAGGAAGCCATGGGATTCACCTACTCTGGTATACGGACT AACGGAGCCACCTCAGCCTGCAGAAGAAGCGGTAGTTCTTTTTATGCCGAAATGAAATGG CTGTTGTCAAACACCGACAATGCTGCCTTCCCACAGATGACCAAATCATACAAGAATACC CGCAAGTCTCCCGCCCTGATTGTGTGGGGCATCCATCACTCGGTGTCCACCGCCGAACAG ACTAAGCTCTACGGCTCAGGGAATAAGCTGGTGACTGTTGGCAGCTCAAACTACCAGCAG TCCTTCGTGCCTAGCCCTGGTGCCCGTCCCCAGGTGAACGGCCAGAGCGGTCGGATTGAC TTCCATTGGCTTATGTTGAACCCAAACGATACCGTGACCTTCTCCTTCAATGGTGCCTTT ATAGCACCCGATCGGGCGTCCTTTCTGCGCGGTAAATCTATGGGGATTCAAAGCGGCGTC CAGGTGGATGCTAATTGTGAAGGAGATTGCTATCACAGCGGGGGAACTATAATTTCTAAC CTGCCATTTCAAAATATTGATAGCCGGGCAGTGGGAAAGTGTCCTCGCTATGTTAAACAA AGATCTCTTTTGCTGGCTACCGGAATGAAGAACGTGCCAGAGATCCCCAAAGGAAGGGGA CTGTTCGGAGCAATCGCCGGGTTTATTGAAAATGGATGGGAGGGCCTCATTGACGGTTGG TACGGGTTCCGCCACCAGAACGCTCAAGGAGAGGGGACGGCAGCGGATTATAAGAGCACT CAGTCCGCAATCGACCAGATCACAGGAAAGCTGAATCGCCTCATTGAGAAAACAAACCAG CAGTTCGAGTTGATTGATAACGAATTCAACGAGGTGGAAAAACAGATCGGCAATGTGATA AACTGGACCCGCGACTCCATTACTGAGGTCTGGTCTTACAACGCAGAACTGCTTGTCGCA ATGGAGAATCAACACACCATAGATCTCGCTGATTCTGAAATGGATAAGCTGTACGAAAGG GTGAAAAGACAGCTGAGAGAGAATGCTGAAGAAGATGGCACCGGTTGCTTCGAGATCTTT CACAAATGTGACGATGACTGCATGGCCTCCATTAGGAATAACACATATGATCATTCCAAG TACAGGGAAGAGGCCATGCAGAACCGGATTCAGATTGATCCGGTTAAGCTGAGTTCCGGG TACAAAGATGTGATACTATGGTTTTCTTTCGGCGCGAGTTGCTTCATTTTGCTTGCCATA GTGATGGGTTTAGTTTTCATCTGCGTGAAGAACGGAAACATGCGCTGCACTATTTGCATA 651 ATGAATACCCAGATTCTTGTTTTTGCTCTTATAGCCATAATACCCACGAACGCAGACAAA ATCTGCTTGGGCCACCACGCAGTATCTAACGGCACCAAGGTGAATACTCTCACCGAACGT GGGGTGGAGGTCGTGAATGCTACAGAAACAGTGGAGCGCACAAACATTCCTCGTATTTGT TCAAAAGGGAAGAAGACAGTGGATCTGGGCCAGTGCGGCCTATTAGGAACAATCACAGGG CCCCCTCAATGTGACCAGTTTCTGGAGTTTTCCGCGGACCTCATTATCGAGCGACGGGAA GGGAGCGACGTATGCTACCCGGGAAAATTCGTCAATGAGGAGGCCCTGCGTCAGATTCTT AGGGAGTCAGGCGGCATCGACAAGGAAGCTATGGGATTTACATATTCTGGAATTCGCACT AACGGCGCCACCTCCGCTTGTCGACGGAGCGGATCGTCCTTCTATGCCGAAATGAAGTGG CTGCTGTCGAATACGGACAACGCTGCTTTTCCACAAATGACTAAGAGCTATAAGAATACC AGAAAGTCTCCTGCGTTAATTGTATGGGGAATACATCATAGTGTGTCTACCGCCGAGCAG ACAAAACTGTACGGTTCCGGCAATAAGCTAGTCACTGTGGGCTCTTCCAATTACCAGCAG TCGTTTGTCCCCTCGCCAGGGGCCCGCCCGCAAGTAAATGGACAATCTGGGCGTATCGAT TTCCATTGGCTTATGCTGAACCCTAATGACACCGTGACATTTTCATTCAATGGGGCTTTC ATTGCCCCCGACAGGGCTAGCTTCCTTCGCGGCAAGAGCATGGGGATACAATCCGGGGTT CAAGTGGATGCCAACTGCGAGGGCGACTGTTACCACTCAGGCGGAACCATCATTTCAAAT CTGCCCTTTCAGAACATTGACAGCCGCGCCGTGGGCAAGTGTCCACGATATGTGAAGCAG AGATCACTGCTCCTTGCAACCGGTATGAAAAATGTTCCTGAGATACCGAAGGGCCGGGGG CTCTTCGGTGCTATCGCTGGATTCATTGAAAACGGGTGGGAAGGACTGATCGACGGTTGG TATGGATTTAGGCACCAGAACGCACAGGGCGAAGGGACCGCCGCTGATTATAAAAGCACG CAGAGCGCTATAGATCAGATCACCGGAAAGCTGAACCGCCTGATCGAGAAAACGAACCAA CAGTTCGAACTGATTGATAACGAGTTTAACGAAGTGGAAAAACAGATTGGTAACGTGATC AACTGGACTAGAGACTCCATCACCGAAGTGTGGTCATATAACGCAGAGTTACTCGTCGCG ATGGAAAACCAACACACCATCGACCTGGCAGACAGTGAGATGGATAAACTCTACGAACGG GTCAAGAGACAACTACGTGAGAATGCCGAGGAAGATGGCACAGGTTGTTTTGAAATTTTT CACAAGTGTGACGACGACTGCATGGCATCAATAAGAAACAATACTTACGACCATAGTAAG TACCGGGAGGAAGCTATGCAGAATAGAATCCAAATAGATCCAGTGAAATTGAGTAGCGGA TATAAGGATGTGATTCTATGGTTTAGCTTCGGCGCTAGTTGTTTTATCCTTTTGGCTATA GTGATGGGGCTCGTTTTTATCTGCGTGAAGAACGGAAACATGAGATGTACGATCTGCATT 652 ATGAATACCCAAATTCTCGTTTTTGCCCTCATCGCCATTATCCCTACTAACGCCGATAAG ATCTGTCTGGGGCATCATGCCGTCTCCAACGGGACCAAGGTAAACACTCTGACCGAGCGC GGTGTCGAAGTAGTCAATGCTACAGAGACAGTTGAACGCACTAATATTCCCAGGATCTGT AGTAAAGGAAAGCGTACCGTGGACCTAGGACAATGTGGCTTGCTCGGCACTATCACCGGC CCTCCACAGTGCGACCAATTTCTGGAATTCTCCGCTGATCTGATTATCGAGAGAAGAGAA GGCAGTGACGTGTGCTACCCGGGAAAGTTTGTCAACGAAGAGGCCTTAAGGCAGATCCTG CGCGAGAGCGGGGGTATAGATAAAGAAGCCATGGGCTTCACTTACAGTGGAATTAGGACA AACGGCGCCACGTCGGCCTGCAGAAGGTCTGGGTCCTCATTCTACGCCGAGATGAAGTGG CTTCTGTCGAATACCGACAATGCAGCATTTCCACAAATGACTAAATCCTATAAGAACACC CGGAAGTCACCAGCCCTCATAGTGTGGGGGATCCATCACTCCGTGAGCACTGCAGAGCAA ACAAAGCTGTATGGGTCCGGGAATAAACTGGTAACCGTTGGCAGTAGCAATTATCAGCAG TCATTTGTTCCCTCCCCAGGTGCCCGGCCTCAGGTGAATGGTCTGTCTGGTCGCATCGAC TTTCACTGGCTGATGCTGAATCCAAATGATACAGTCACATTTTCGTTTAATGGAGCCTTC ATCGCGCCCGACAGGGCTAGCTTCCTACGCGGCAAGAGCATGGGCATTCAGAGCGGCGTC CAGGTTGACGCCAATTGCGAGGGAGATTGTTATCATAGCGGAGGCACAATCATCTCAAAC CTCCCCTTTCAGAATATAGACTCCAGAGCCGTTGGGAAGTGCCCTAGATACGTGAAACAG CGATCCCTGCTCCTAGCTACAGGAATGAAGAATGTGCCAGAAATCCCCAAGGGTCGGGGG CTCTTTGGAGCCATCGCCGGTTTTATCGAAAATGGTTGGGAAGGCCTCATTAATGGCTGG TACGGCTTTCGACACCAGAATGCCCAGGGTGAAGGAACAGCGGCAGACTATAAGTCCACA CAGAGTGCTATAGACCAGATCACCGGCAAGCTTAACAGACTGATTGAAAAGACCAATCAG CAGTTCGAGTTGATCGACAACGAATTCAACGAGGTTGAGAAACAAATAGGAAACGTGATA AATTGGACCCGCGATTCTATAACAGAAGTGTGGTCATATAATGCGGAACTGCTCGTGGCA ATGGAGAACCAACATACAATAGACCTTGCAGACTCCGAAATGGATAAGCTGTACGAGCGC GTCAAGCGACAGCTCAGAGAAAATGCAGAGGAGGATGGAACAGGCTGTTTTGAAATTTTC CACAAGTGTGACGACGATTGCATGGCCTCCATCAGAAATAACACATATGACCATTCAAAG TATCGCGAAGAAGCTATGCAGAATCGAATCCAAATAGATCCTGTGAAGTTGTCGTCCGGC TACAAAGATGTTATCCTGTGGTTCAGTTTCGGGGCCTCATGCTTCATCCTGCTGGCCATA GTGATGGGTCTCGTGTTCATCTGCGTGAAGAACGGCAACATGCGCTGCACTATCTGCATT 653 ATGAATACCCAGATTTTGGTGTTCGCACTTATCGCAATAATCCCGACTAACGCTGATAAA ATTTGTTTAGGACATCATGCCGTTTCTAACGGAACTAAGGTGAACACACTTACCGAGAGA GGTGTGGAAGTGGTGAACGCTACCGAAACTGTGGAGCGGACTAACATCCCCCGGATATGC TCAAAGGGCAAGAGAACTGTGGATTTAGGTCAATGTGGTCTACTGGGCACAATTACCGGC CCACCCCAATGCGACCAGTTCCTGGAGTTTAGCGCCGACCTGATTATTGAGAGACGTGAG GGCTCAGACGTATGTTATCCTGGGAAATTTGTCAACGAAGAAGCCTTGCGGCAGATCCTA CGTGAGAGCGGGGGCATTGACAAAGAGGCCATGGGGTTTACATACTCAGGCATCCGAACT AACGGGGCAACAAGTGCATGTAGACGATCTGGGTCTAGCTTCTATGCCGAGATGAAATGG CTCCTCTCGAACACCGATAACGCCGCTTTTCCGCAGATGACTAAATCTTATAAGAATACA AGGAAGTCCCCCGCTTTAATTGTCTGGGGCATCCACCACTCTGTGAGCACCGCCGAACAG ACAAAATTGTACGGCTCGGGGTCCAAGCTTGTCACTGTGGGCTCATCCAATTACCAGCAA AGCTTTGTGCCCTCCCCCGGGGCAAGACCTCAGGTGAACGGGTTGAGCGGAAGGATTGAT TTCCATTGGCTGATGTTGAACCCTAACGACACAGTCACCTTCTCGTTTAACGGGGCCTTC ATTGCCCCAGATAGGGCCTCTTTTCTGCGCGGAAAGTCGATGGGGATCCAGTCAGGGGTG CAGGTGGACGCCAACTGTGAAGGCGACTGTTATCACAGCGGAGGAACGATAATTTCCAAT CTACCCTTTCAGAATATAGATTCAAGAGCCGTTGGGAAATGTCCCAGGTACGTCAAGCAG AGGTCGCTCCTCTTGGCTACCGGCATGAAGAATGTTCCTGAAATCCCGAAGGGCAGAGGA CTCTTTGGCGCCATAGCCGGCTTTATTGAAAATGGATGGGAAGGATTAATTGACGGCTGG TACGGCTTCCGGCATCAGAATGCACAGGGCGAGGGCACGGCGGCTGACTACAAGTCTACT CAGAGTGCCATAGACCAGATTACCGGGAAGTTAAATCGTCTGATCGAGAAGACCAACCAA CAGTTTGAACTCATTGACAATGAGTTCAACGAAGTGGAGAAACAGATCGGCAACGTAATC AATTGGACTCGCGATTCCATTACCGAGGTGTGGTCTTATAACGCAGAACTCTTGGTGGCC ATGGAAAACCAACACACGATTGATCTCGCAGACAGCGAGATGGACAAGTTGTATGAGAGA GTTAAGCGCCAGCTCAGGGAGAATGCCGAAGAGGACGGAACCGGTTGCTTTGAGATCTTT CACAAATGTGATGATGACTGCATGGCGAGCATTCGTAATAATACTTATGACCATAGTAAA TACCGGGAGGAAGCCATGCAGAATCGCATCCAAATTGACCCCGTAAAGCTAAGTTCAGGT TATAAGGATGTTATTCTTTGGTTTTCATTCGGAGCTTCATGCTTCATCCTTCTTGCAATT GTAATGGGACTGGTTTTCATTTGTGTAAAGAACGGAAATATGCGATGTACGATTTGTATT 654 ATGAATACTCAAATCCTTGTCTTTGCGCTGATCGCTATCATTCCAACAAATGCAGATAAA ATCTGTCTAGGACATCATGCTGTGTCAAACGGTACTAAAGTGAATACACTGACGGAGAGG GGAGTCGAGGTGGTGAACGCAACAGAGACAGTGGAACGCACAAATATCCCCCGCATCTGT TCTAAGGGGAAAAAAACCGTGGACTTGGGGCAGTGCGGTTTACTGGGGACCATTACTGGT CCGCCCCAGTGCGACCAGTTCCTAGAGTTTTCCGCAGACCTGATTATAGAGAGACGCGAA GGAAGCGACGTATGTTACCCCGGGAAGTTTGTCAATGAAGAAGCCCTCAGACAGATTCTT CGGGAGTCCGGAGGCATCGATAAAGAGGCTATGGGCTTCACCTACTCCGGCATTCGTACA AATGGTGCTACGTCTGCCTGTCGACGCAGTGGGTCATCCTTTTACGCCGAAATGAAGTGG CTATTGAGCAATACCGACAACGCAGCTTTCCCTCAGATGACTAAGAGCTATAAAAACACC CGCAAGAGCCCAGCTCTGATCGTATGGGGAATTCACCACTCAGTTTCGACTGCAGAGCAG ACTAAACTGTATGGCTCCGGGAATAAGCTGGTTACCGTGGGTAGCTCTAACTACCAGCAG TCATTCGTTCCTTCACCCGGCGCACGCCCCCAAGTGAATGGGCAATCTGGGCGCATAGAC TTCCACTGGCTTATGCTAAACCCAAACGACACTGTGACCTTTTCATTCAACGGCGCATTC ATTGCACCTGACCGCGCGTCATTTCTCCGGGGCAAGAGCATGGGGATCCAGAGCGGCGTA CAGGTGGACGCGAATTGCGAGGGGGATTGCTACCATTCAGGAGGAACCATTATTTCTAAC CTCCCGTTCCAAAATATAGACTCTCGTGCTGTGGGAAAGTGCCCGAGATACGTCAAACAG CGTTCTCTACTCCTGGCTACGGGGATGAAGAACGTGCCCGAGATTCCGAAAGGGCGCGGA CTGTTTGGCGCCATCGCGGGATTTATTGAGAACGGCTGGGAGGGGCTTATTGATGGTTGG TATGGCTTCCGGCACCAGAACGCTCAGGGGGAGGGGACTGCAGCTGATTACAAGTCAACA CAATCAGCAATCGATCAGATTACCGGAAAGCTGAACAGACTCATCGAGAAGACGAATCAA CAGTTTGAATTGATCGATAACGAATTCAACGAAGTCGAGAAACAAATCGGAAACGTCATT AACTGGACTAGAGATTCCATCACCGAGGTGTGGTCTTATAACGCCGAGCTCCTGGTGGCG ATGGAGAACCAGCACACAATTGATCTCGCTGACAGCGAGATGGACAAGTTGTACGAGAGG GTAAAACGACAGCTCCGGGAAAATGCCGAGGAAGATGGGACAGGGTGCTTCGAGATCTTT CACAAGTGTGACGACGACTGTATGGCCTCAATTCGAAATAACACCTATGATCACTCGAAA TACCGCGAGGAAGCTATGCAGAACAGAATCCAGATTGACCCTGTGAAGCTGAGCAGTGGG TATAAAGACGTCATCTTATGGTTCAGCTTCGGGGCTTCTTGCTTCATACTGCTTGCCATC GTTATGGGCCTGGTGTTTATCTGTGTCAAGAATGGTAACATGAGGTGCACTATCTGTATA 655 ATGAACACCCAAATTCTTGTATTTGCTCTGATCGCCATTATTCCAACCAATGCCGACAAG ATCTGTTTGGGGCACCATGCCGTTTCTAATGGCACAAAAGTCAATACATTAACTGAGCGC GGCGTAGAAGTCGTGAACGCTACCGAAACAGTTGAGAGAACCAACATCCCTCGAATATGT TCCAAGGGGAAGAAAACAGTGGATCTCGGGCAGTGCGGCTTGCTGGGAACAATAACTGGC CCGCCTCAGTGTGATCAGTTCCTGGAATTTAGTGCTGACCTGATAATCGAGCGAAGAGAG GGGAGCGATGTGTGTTATCCCGGGAAATTTGTAAACGAGGAGGCCCTGCGGCAGATACTT AGAGAGAGTGGGGGAATCGACAAAGAAGCGATGGGGTTTACCTACTCTGGAATCAGAACT AACGGGGCTACAAGCGCCTGCCGGCGCAGCGGATCGTCCTTCTACGCAGAGATGAAGTGG CTGCTCAGCAACACTGACAATGCCGCTTTTCCTCAAATGACCAAGTCTTACAAGAACACC CGTAAAAGTCCCGCGCTCATAGTATGGGGTATCCACCATTCTGTCTCAACAGCAGAACAG ACCAAACTGTACGGCAGCGGCAACAAACTGGTGACAGTGGGATCTAGCAATTACCAGCAG AGTTTTGTCCCATCCCCTGGCGCGCGGCCCCAGGTGAATGGGCAAAGTGGACGGATAGAC TTCCACTGGTTGATGCTGAACCCAAATGATACCGTGACATTTTCTTTCAACGGTGCATTT ATAGCCCCTGACCGTGCAAGCTTCTTGAGAGGTAAGAGCATGGGAATTCAGTCAGGTGTT CAGGTGGATGCCAATTGCGAGGGCGATTGCTACCACAGCGGCGGCACTATTATTTCTAAT CTTCCTTTCCAGAATATAGACTCCCGTGCTGTGGGTAAATGCCCTAGGTACGTAAAGCAA AGGAGCTTACTGTTGGCAACAGGCATGAAGAATGTGCCAGAAATTCCCAAGGGGCGGGGC CTGTTTGGCGCCATTGCAGGCTTTATTGAGAATGGCTGGGAGGGCCTAATTGATGGTTGG TACGGCTTCAGGCACCAGAACGCACAGGGGGAAGGCACAGCTGCGGATTACAAAAGTACC CAGAGCGCCATAGATCAAATAACCGGCAAGTTAAACCGATTGATTGAGAAAACAAACCAG CAATTTGAGCTGATAGACAATGAATTCAACGAAGTCGAAAAGCAGATTGGCAACGTGATC AATTGGACCCGGGATAGCATTACTGAGGTATGGAGCTATAATGCAGAGTTGCTGGTGGCC ATGGAAAACCAGCATACCATCGATCTGGCCGACTCAGAAATGGATAAGCTCTACGAGCGG GTGAAGAGGCAGCTGAGAGAAAATGCCGAAGAAGACGGAACCGGCTGCTTTGAGATTTTT CACAAGTGCGACGATGATTGCATGGCCAGTATTAGAAACAACACCTATGATCACTCCAAG TACCGCGAAGAAGCCATGCAGAACCGCATCCAAATCGATCCGGTCAAACTCTCCTCTGGC TATAAGGATGTAATCCTGTGGTTCTCTTTTGGAGCGTCCTGCTTCATATTATTGGCTATT GTGATGGGCTTGGTGTTTATCTGTGTTAAGAACGGAAACATGCGGTGTACAATCTGCATT 656 ATGAATACACAGATACTCGTGTTCGCCCTTATTGCTATCATCCCTACAAATGCTGACAAG ATATGTCTGGGCCACCACGCCGTGAGCAATGGCACCAAGGTTAATACCCTAACCGAACGG GGAGTTGAGGTGGTTAACGCTACCGAGACCGTAGAGCGCACTAATATTCCACGCATTTGC TCGAAAGGCAAGAAAACAGTGGACTTAGGCCAATGTGGACTCCTCGGAACAATAACCGGC CCACCACAGTGCGATCAGTTCCTCGAGTTTTCAGCCGACCTAATTATTGAGCGACGGGAA GGTAGCGATGTGTGTTATCCAGGGAAGTTCGTCAATGAAGAGGCCTTGCGGCAGATACTG CGCGAAAGTGGGGGCATAGACAAGGAGGCTATGGGGTTTACATACAGTGGAATTCGCACC AATGGGGCCACTAGCGCCTGTAGGAGATCAGGCTCCTCTTTCTACGCTGAGATGAAATGG TTACTGTCAAATACTGATAACGCCGCCTTTCCTCAGATGACAAAATCCTATAAGAACACT AGGAAGTCACCTGCTCTAATCGTTTGGGGAATCCATCACTCCGTGAGCACCGCTGAGCAG ACCAAGCTTTATGGCTCAGGAAACAAGCTCGTGACGGTGGGCTCCAGTAACTATCAACAA AGCTTCGTGCCTTCTCCAGGAGCAAGGCCCCAGGTGAATGGACAGTCCGGGAGAATCGAC TTTCACTGGCTCATGCTGAATCCAAACGATACCGTTACCTTTTCATTCAATGGGGCCTTC ATCGCCCCAGACAGGGCCAGCTTCCTCCGCGGCAAAAGCATGGGCATACAAAGCGGCGTG CAGGTGGATGCTAATTGCGAGGGTGACTGCTATCATTCAGGCGGCACCATAATCAGTAAC CTGCCCTTTCAAAATATAGATTCGCGGGCAGTAGGTAAATGCCCTCGTTATGTGAAACAG CGGTCCTTGCTGCTTGCGACTGGAATGAAAAACGTGCCCGAGATTCCCAAGGGCCGTGGA TTATTTGGCGCTATCGCCGGGTTCATCGAGAACGGCTGGGAGGGTCTCATTGATGGATGG TACGGTTTCAGACACCAGAACGCCCAGGGGGAGGGGACCGCAGCCGACTACAAATCAACC CAGTCCGCCATTGATCAGATCACAGGGAAGCTAAATCGCCTGATTGAGAAGACAAATCAG CAGTTCGAGCTGATCGACAACGAATTCAATGAGGTAGAGAAACAGATTGGGAACGTTATT AATTGGACCAGAGATTCCATAACAGAGGTATGGTCTTATAACGCAGAACTGCTCGTTGCG ATGGAGAACCAGCATACAATCGACCTGGCAGACAGTGAAATGGACAAGCTCTATGAGAGG GTCAAGAGGCAATTGAGAGAGAATGCCGAAGAAGACGGGACCGGTTGCTTCGAGATCTTC CACAAATGTGATGATGACTGCATGGCAAGCATTAGAAACAACACCTACGATCACTCCAAA TACCGAGAGGAGGCTATGCAAAATCGGATACAGATCGATCCTGTCAAGCTGTCTTCTGGT TACAAAGATGTTATTCTGTGGTTCAGTTTTGGGGCCTCATGTTTCATCTTACTGGCAATC GTGATGGGACTCGTTTTCATCTGTGTTAAAAATGGCAACATGAGGTGTACCATTTGTATC 657 ATGAACACACAAATTTTAGTGTTTGCTCTGATTGCCATTATCCCCACCAACGCTGATAAG ATTTGTCTGGGGCACCACGCAGTGTCTAATGGCACCAAAGTCAACACACTTACAGAGAGA GGAGTGGAGGTGGTTAACGCCACTGAAACCGTCGAGAGAACCAATATTCCTCGGATCTGC TCCAAGGGCAAGAAAACAGTTGATCTAGGACAGTGTGGGTTGCTAGGGACAATCACCGGA CCACCTCAGTGTGATCAGTTCTTAGAGTTCTCCGCTGATCTAATTATTGAGCGAAGAGAA GGGTCCGATGTGTGCTACCCCGGTAAATTTGTCAATGAAGAAGCCTTGAGGCAGATTCTG AGAGAAAGCGGCGGCATCGATAAGGAGGCAATGGGTTTCACTTACTCTGGAATCCGGACC AACGGAGCCACTAGCGCTTGTCGAAGGAGTGGATCGTCCTTCTACGCCGAGATGAAATGG CTCTTGTCAAATACAGATAATGCCGCATTTCCCCAGATGACTAAGAGCTACAAGAATACA CGTAAGAGCCCGGCTCTGATCGTCTGGGGTATTCATCATAGTGTGTCTACTGCAGAGCAG ACCAAACTATACGGTAGTGGCAACAAACTTGTCACCGTCGGCAGTTCTAATTACCAGCAA TCCTTTGTCCCTTCCCCCGGCGCTCGGCCTCAGGTGAATGGACAGAGCGGCAGGATTGAC TTCCACTGGCTTATGCTGAACCCTAATGATACTGTTACCTTCTCGTTTAATGGGGCGTTT ATTGCTCCCGATAGGGCCAGTTTTCTTCGGGGCAAGTCCATGGGGATCCAGTCAGGTGTG CAGGTCGATGCTAATTGTGAGGGCGACTGCTATCATTCTGGCGGCACGATCATCTCAAAC TTGCCCTTCCAAAATATAGATAGCCGAGCAGTGGGAAAATGCCCTCGTTACGTCAAGCAG AGGAGCCTCCTGTTAGCCACCGGGATGAAAAATGTTCCAGAAATACCCAAGGGGAGGGGC TTATTTGGCGCTATTGCAGGATTTATCGAGAACGGTTGGGAGGGACTCATTGACGGATGG TATGGCTTCCGCCACCAGAACGCCCAGGGGGAGGGTACCGCAGCTGATTACAAGTCCACA CAGAGTGCCATAGATCAAATCACCGGTAAGCTGAATAGGCTGATCGAAAAAACCAATCAG CAGTTTGAGCTCATCGATAATGAGTTCAACGAGGTGGAGAAACAGATTGGTAATGTCATC AACTGGACAAGGGACTCGATTACCGAAGTGTGGAGCTATAACGCAGAGCTCTTGGTTGCC ATGGAGAATCAGCACACCATCGATTTAGCAGATAGCGAAATGGACAAACTATACGAAAGG GTGAAACGGCAACTTAGGGAGAACGCCGAAGAGGATGGGACCGGGTGCTTCGAAATTTTT CACAAGTGTGATGACGACTGCATGGCCTCTATCCGGAATAATACCTACGATCACAGCAAA TACAGGGAGGAAGCCATGCAGAACCGCATCCAGATCGATCCAGTCAAGCTGTCTTCTGGC TATAAGGACGTGATCCTGTGGTTCTCTTTCGGCGCTAGTTGTTTTATCCTGCTGGCCATC GTGATGGGCCTTGTTTTCATCTGTGTGAAAAACGGGAATATGAGGTGCACAATCTGCATT 658 ATGAACACACAGATCCTCGTCTTTGCACTCATCGCAATCATCCCCACCAACGCTGATAAA ATTTGTCTCGGACATCATGCCGTGAGCAATGGGACCAAAGTTAACACCCTAACGGAGAGA GGTGTCGAGGTGGTGAACGCGACAGAAACCGTAGAACGAACCAATATTCCAAGGATCTGC AGTAAGGGAAAAAGGACCGTGGATTTGGGGCAGTGTGGATTGCTGGGGACTATCACAGGA CCACCACAGTGCGACCAATTCCTTGAATTTTCCGCGGATCTGATTATTGAGAGGAGGGAG GGATCTGACGTCTGTTACCCAGGCAAGTTCGTTAATGAGGAAGCGCTGAGACAGATTCTG CGAGAGAGCGGAGGCATAGACAAAGAGGCTATGGGTTTTACCTATTCTGGGATACGCACA AACGGAGCTACAAGCGCATGCCGGAGAAGTGGAAGCTCATTTTATGCGGAAATGAAATGG CTCCTCTCCAACACCGACAATGCAGCATTCCCTCAGATGACCAAATCATATAAAAACACC AGAAAAAGTCCGGCTCTCATAGTGTGGGGTATACATCATTCCGTCTCGACCGCAGAGCAA ACTAAGCTCTACGGCTCTGGAAACAAACTCGTGACTGTCGGCAGTTCTAATTACCAGCAG TCTTTTGTACCTAGCCCCGGGGCTAGGCCACAGGTGAATGGCTTATCTGGGCGCATAGAC TTCCACTGGCTTATGCTGAACCCAAACGATACAGTGACCTTCTCCTTTAACGGCGCCTTC ATTGCCCCCGACAGAGCTAGTTTCCTGCGCGGAAAATCAATGGGAATCCAGAGTGGGGTG CAGGTGGATGCAAACTGCGAAGGCGACTGCTATCACTCAGGCGGCACAATAATTAGTAAC CTACCATTCCAGAACATTGATTCACGCGCCGTCGGGAAGTGTCCGAGATACGTGAAACAG CGGTCTCTCCTGTTAGCAACAGGCATGAAGAATGTGCCTGAGATTCCCAAAGGCCGGGGG CTCTTCGGAGCCATTGCTGGTTTCATCGAGAACGGGTGGGAGGGTCTGATCGATGGCTGG TATGGTTTCCGGCATCAGAACGCGCAGGGGGAGGGCACAGCCGCAGATTACAAGAGTACT CAGAGTGCCATCGATCAGATTACAGGGAAGCTGAATAGAATAATCGAAAAAACTAATCAG CAGTTTGAACTGATAGACAACGAATTCAACGAGGTCGAGAAGCAGATCGGGAATGTGATC AACTGGACCCGCGACTCAATCACAGAGGTTTGGAGTTATAATGCCGAGCTCCTCGTTGCC ATGGAGAATCAACATACAATTGACCTTGCTGACTCTGAGATGGATAAACTGTATGAACGA GTTAAGCGACAGTTGAGGGAGAATGCGGAAGAAGACGGGACCGGCTGCTTCGAAATATTC CATAAGTGCGACGATGACTGTATGGCATCAATCAGGAACAACACCTATGACCACTCCAAG TATCGAGAGGAAGCGATGCAGAACAGGATCCAGATCGATCCAGTCAAGTTGTCCTCTGGC TATAAGGACGTGATTCTGTGGTTTTCTTTCGGCGCAAGCTGTTTCATTTTATTAGCTATC GTCATGGGTCTAGTGTTCATCTGTGTTAAAAATGGCAATATGCGATGTACAATCTGTATT 659 ATGAACACCCAAATCCTTGTTTTCGCTCTGATTGCAATTATCCCAACGAATGCTGACAAA ATTTGCCTGGGCCACCACGCTGTGTCCAACGGAACTAAGGTAAATACTCTGACTGAACGC GGCGTGGAGGTGGTGAACGCCACCGAAACAGTGGAGAGAACTAATATTCCCCGCATCTGT TCTAAGGGCAAAAAGACAGTGGATCTCGGTCAGTGCGGGCTGTTGGGAACAATTACCGGA CCTCCCCAATGCGATCAGTTCCTAGAGTTTTCCGCCGACCTGATAATCGAAAGACGTGAA GGCTCTGACGTGTGTTACCCCGGAAAGTTTGTGAATGAAGAAGCACTGCGGCAGATCTTA CGCGAGAGTGGCGGCATTGACAAGGAGGCAATGGGATTTACCTACTCCGGAATCAGGACA AATGGCGCAACCAGTGCTTGTAGGCGCTCCGGAAGCTCCTTTTATGCCGAGATGAAATGG CTTCTGTCCAACACGGACAACGCCGCTTTCCCTCAAATGACCAAATCCTACAAAAATACC CGTAAGTCACCGGCGCTGATTGTATGGGGGATACACCACAGTGTTTCTACCGCCGAACAA ACCAAGCTGTACGGCAGCGGAAATAAACTGGTAACTGTCGGATCATCCAATTACCAGCAG TCCTTCGTCCCTAGCCCTGGGGCGCGCCCGCAGGTCAATGGGCAGTCTGGAAGAATTGAC TTTCATTGGCTGATGTTAAATCCAAACGACACAGTTACATTCAGTTTCAACGGGGCCTTT ATTGCACCCGATAGAGCATCCTTTCTGCGAGGCAAAAGTATGGGGATTCAATCTGGGGTG CAGGTTGATGCGAATTGCGAGGGAGATTGCTATCACTCTGGCGGAACCATCATCAGCAAC CTCCCATTCCAAAATATTGACTCACGCGCTGTGGGAAAGTGCCCTAGGTATGTGAAGCAG CGGTCCTTGCTTTTAGCTACCGGAATGAAAAACGTGCCAGAAATCCCTAAGGGGCGCGGA TTATTCGGCGCCATTGCTGGCTTCATTGAGAATGGATGGGAGGGCCTAATCGACGGTTGG TATGGTTTTCGTCATCAGAACGCACAAGGGGAAGGGACTGCTGCCGACTACAAGTCTACC CAGTCCGCTATAGACCAGATTACCGGTAAGCTAAATCGGCTTATAGAGAAGACTAACCAA CAGTTCGAGCTGATCGACAACGAATTTAACGAAGTGGAGAAGCAGATTGGGAACGTCATC AACTGGACGCGAGACTCTATTACTGAAGTCTGGTCTTACAATGCTGAGTTGCTCGTGGCT ATGGAAAACCAGCATACTATAGACCTGGCCGACTCAGAGATGGATAAGTTATATGAACGC GTGAAGCGGCAGCTCCGAGAAAATGCCGAAGAGGACGGAACAGGGTGTTTTGAGATCTTC CACAAATGTGACGATGACTGCATGGCATCTATACGGAACAATACCTATGACCATTCCAAG TACCGTGAGGAAGCCATGCAAAATAGAATACAAATCGATCCAGTCAAACTCTCTAGCGGC TACAAGGACGTTATCTTGTGGTTCTCCTTCGGAGCGAGCTGTTTTATTTTGCTCGCGATT GTGATGGGATTGGTGTTTATTTGCGTTAAAAACGGAAACATGCGGTGCACCATCTGTATC 660 ATGAATACCCAGATCCTGGTCTTCGCTCTGATCGCAATCATTCCTACCAACGCTGACAAA ATTTGCCTGGGCCACCACGCAGTTAGTAATGGAACAAAAGTGAATACTCTTACAGAGCGG GGTGTCGAGGTAGTAAACGCTACGGAAACCGTAGAGCGCACAAATATCCCCAGAATCTGT AGCAAAGGTAAAAGGACAGTAGACTTGGGCCAGTGTGGACTGCTCGGAACAATTACAGGC CCCCCTCAGTGTGATCAGTTCCTGGAATTCTCAGCCGACCTTATCATCGAACGAAGGGAG GGGAGCGATGTCTGCTACCCAGGCAAGTTTGTGAATGAAGAGGCCCTTCGTCAAATACTC CGAGAATCGGGGGGAATCGATAAAGAAGCAATGGGATTTACCTATAGCGGAATCAGAACT AACGGCGCAACTTCCGCCTGCAGGCGGTCTGGCAGCTCCTTTTATGCCGAGATGAAGTGG CTATTGAGCAATACTGACAACGCAGCCTTCCCTCAAATGACCAAGTCATACAAAAATACA CGCAAGTCTCCAGCTCTGATCGTGTGGGGCATTCACCATAGCGTCAGCACAGCCGAGCAA ACAAAGCTCTACGGCAGCGGCAACAAACTCGTGACCGTCGGCAGTTCTAACTACCAGCAG TCCTTTGTGCCCAGCCCAGGGGCCCGTCCACAGGTTAACGGACTGTCTGGCCGGATCGAT TTCCACTGGCTGATGTTAAATCCCAACGACACAGTCACGTTTAGCTTTAACGGAGCCTTT ATCGCCCCCGACAGGGCTAGCTTTCTTAGGGGCAAGAGCATGGGAATTCAATCAGGGGTT CAAGTGGACGCAAACTGCGAGGGCGATTGCTATCACTCCGGTGGAACTATTATAAGTAAT CTACCATTCCAAAACATCGATTCAAGGGCGGTGGGTAAGTGTCCTCGCTACGTTAAGCAG CGCAGCCTGCTACTCGCGACGGGAATGAAAAATGTCCCGGAGATACCTAAAGGCAGAGGC CTCTTCGGCGCCATCGCAGGTTTCATCGAAAACGGCTGGGAAGGTCTGATCGACGGTTGG TATGGATTCCGTCACCAAAACGCACAGGGAGAGGGTACAGCCGCAGACTATAAGTCTACC CAGTCAGCTATCGACCAAATTACTGGAAAACTGAATCGTATCATTGAAAAGACCAATCAA CAATTCGAGCTGATCGACAACGAGTTTAATGAAGTTGAGAAACAGATCGGAAATGTGATT AACTGGACACGTGACAGCATTACTGAGGTCTGGAGCTACAACGCGGAACTTCTCGTAGCG ATGGAGAACCAGCACACTATTGACCTGGCTGATAGTGAAATGGATAAACTATATGAAAGG GTCAAAAGACAACTGCGGGAAAATGCCGAGGAAGATGGTACTGGATGTTTTGAAATCTTT CACAAGTGCGATGACGACTGTATGGCTAGCATCAGGAACAATACATACGACCATTCGAAG TATCGCGAAGAGGCCATGCAGAACCGAATACAGATTGATCCGGTTAAGCTGTCTTCTGGA TATAAAGACGTCATCCTGTGGTTTAGTTTCGGGGCGAGTTGTTTCATTCTACTGGCTATT GTCATGGGCCTGGTTTTTATCTGCGTGAAAAATGGCAACATGCGGTGCACGATCTGCATC 661 ATGAACACACAGATCTTGGTGTTCGCCCTCATCGCGATAATACCCACTAATGCCGACAAA ATTTGTTTGGGTCATCACGCCGTGAGCAATGGCACTAAGGTGAACACGCTTACAGAACGG GGCGTAGAAGTTGTGAACGCCACAGAGACAGTGGAGAGGACAAATATCCCGCGGATCTGC TCAAAGGGGAAAAAAACCGTTGACCTGGGACAGTGCGGCCTGCTGGGGACAATAACAGGC CCCCCCCAGTGTGACCAATTTCTGGAGTTCTCTGCCGACCTGATTATCGAAAGACGGGAG GGCAGTGATGTCTGCTACCCCGGCAAGTTCGTAAATGAAGAGGCTCTGCGGCAGATCCTA CGGGAGTCCGGAGGAATCGATAAGGAGGCAATGGGGTTTACGTATAGCGGCATTAGAACC AACGGAGCAACCAGTGCTTGCAGGAGGAGCGGCAGCTCATTCTACGCGGAAATGAAGTGG CTGCTGTCAAATACAGATAACGCCGCTTTCCCACAGATGACTAAATCCTATAAGAACACC CGCAAGAGTCCTGCTCTCATCGTTTGGGGTATCCACCACTCTGTGTCAACTGCCGAGCAG ACCAAACTTTACGGATCTGGGAATAAGCTTGTGACAGTTGGGAGCAGCAACTATCAGCAG TCATTTGTGCCCTCTCCGGGTGCCAGGCCACAGGTTAATGGACAGTCGGGGCGTATCGAC TTCCATTGGCTTATGCTCAATCCTAATGACACTGTTACCTTTTCTTTCAACGGCGCGTTC ATTGCCCCCGACAGAGCGAGCTTTCTTAGGGGGAAATCGATGGGTATTCAGAGCGGGGTC CAGGTCGATGCGAACTGCGAGGGCGATTGCTACCACTCAGGGGGAACAATTATCTCTAAT TTACCCTTTCAGAACATCGACTCAAGGGCAGTGGGGAAGTGTCCGCGATACGTTAAACAA CGGAGTTTGCTCCTGGCCACAGGCATGAAAAACGTCCCAGAAATCCCCAAAGGCAGAGGG TTGTTTGGGGCGATCGCCGGCTTTATCGAGAACGGATGGGAAGGCTTAATTGACGGCTGG TACGGCTTCCGCCACCAGAACGCTCAGGGGGAAGGTACCGCCGCTGATTATAAAAGTACG CAAAGCGCTATTGATCAGATTACGGGCAAATTGAATCGGCTGATTGAGAAAACAAATCAG CAGTTTGAACTGATCGACAACGAGTTTAATGAGGTGGAGAAGCAGATAGGAAATGTAATT AACTGGACTCGGGATTCGATCACGGAGGTTTGGTCCTATAACGCAGAGCTACTGGTCGCC ATGGAGAATCAGCACACTATTGACCTGGCAGATTCTGAGATGGACAAGCTGTACGAGAGG GTAAAAAGACAACTGCGGGAGAACGCTGAAGAGGATGGAACAGGGTGTTTTGAGATCTTT CACAAGTGCGACGATGATTGCATGGCATCTATCCGCAACAATACTTACGACCACTCTAAG TACAGAGAAGAGGCGATGCAGAATCGAATTCAGATTGACCCGGTGAAGCTGAGCAGTGGA TATAAAGATGTAATCCTCTGGTTTAGCTTCGGAGCCTCATGTTTTATCCTCCTTGCTATC GTTATGGGCCTCGTCTTTATATGTGTCAAAAACGGCAATATGCGCTGCACAATCTGCATT 662 ATGAATACCCAAATTTTGGTTTTTGCTCTGATTGCCATTATTCCCACTAATGCCGACAAG ATCTGCCTCGGCCATCATGCCGTGTCTAATGGCACAAAGGTGAATACCTTGACAGAAAGG GGTGTGGAAGTAGTGAATGCCACAGAAACTGTAGAGCGGACCAATATTCCCAGGATTTGC TCTAAGGGAAAGAAGACCGTTGATCTGGGCCAATGCGGCTTGCTGGGCACCATCACTGGG CCACCACAGTGCGACCAGTTCCTGGAATTTAGCGCCGATCTGATAATAGAGAGACGGGAA GGTAGCGACGTCTGCTATCCTGGGAAATTCGTCAACGAGGAAGCTCTGCGGCAGATCCTA CGGGAGAGTGGCGGGATAGACAAGGAGGCAATGGGCTTTACGTACTCAGGAATTCGAACC AATGGGGCGACGTCCGCCTGCCGGAGATCGGGCTCTTCTTTTTACGCAGAAATGAAGTGG CTGCTGTCGAATACAGATAATGCGGCTTTCCCCCAGATGACCAAGTCATATAAAAATACG AGAAAATCGCCCGCACTTATTGTGTGGGGCATCCACCACTCCGTGTCAACTGCCGAGCAA ACCAAGCTATATGGCAGCGGCAATAAGCTGGTGACAGTAGGAAGTTCTAATTACCAGCAG TCTTTCGTGCCGAGCCCTGGAGCCAGACCACAGGTGAATGGCCAGTCGGGCAGGATAGAT TTCCACTGGTTAATGCTTAACCCAAACGACACGGTGACCTTCAGTTTCAACGGTGCCTTC ATCGCCCCCGATCGCGCCTCCTTTTTGCGCGGCAAGTCTATGGGTATTCAGAGTGGAGTG CAGGTGGACGCAAACTGCGAAGGGGATTGTTATCACAGCGGCGGGACCATAATCAGCAAT CTCCCGTTTCAAAATATCGATTCTCGGGCAGTCGGTAAATGTCCCAGGTACGTTAAGCAA CGGAGCCTGCTGCTCGCTACAGGCATGAAGAATGTGCCCGAGATCCCCAAGGGAAGAGGC CTGTTCGGGGCCATCGCTGGTTTCATCGAGAACGGATGGGAGGGATTAATCGACGGGTGG TACGGTTTCCGACACCAGAACGCACAGGGTGAGGGCACTGCCGCTGATTACAAATCAACC CAGTCTGCAATCGACCAGATCACTGGGAAATTGAACCGATTGATCGAAAAGACGAACCAG CAGTTCGAACTCATTGACAACGAGTTTAATGAAGTCGAGAAGCAGATTGGAAATGTGATC AACTGGACAAGGGATTCTATCACAGAGGTCTGGTCATACAACGCTGAACTCCTTGTGGCC ATGGAGAACCAGCACACCATCGATCTGGCTGATTCAGAAATGGATAAACTATATGAAAGG GTGAAGCGGCAACTTAGGGAAAATGCTGAGGAGGACGGCACGGGATGCTTTGAAATCTTC CACAAGTGTGATGATGACTGTATGGCGTCCATCCGGAACAATACATATGACCATTCAAAA TATAGAGAAGAGGCAATGCAGAACAGGATACAGATTGACCCTGTCAAGTTGAGTTCTGGC TACAAGGACGTGATTCTGTGGTTCAGCTTCGGAGCCAGTTGTTTCATCCTCCTGGCCATC GTGATGGGCCTAGTGTTCATCTGCGTGAAAAATGGCAATATGCGCTGCACAATATGTATA 663 ATGAATACCCAAATCCTCGTTTTCGCACTGATTGCTATTATACCCACCAACGCTGACAAG ATTTGTCTGGGTCACCACGCAGTTTCTAACGGCACAAAGGTGAATACTCTCACAGAGCGC GGGGTTGAGGTCGTCAACGCTACTGAGACCGTCGAACGAACCAATATCCCCAGGATCTGT AGCAAGGGAAAGAAAACAGTCGATTTAGGCCAGTGTGGCCTCTTAGGCACCATCACAGGC CCACCCCAATGCGACCAGTTCCTGGAGTTCTCCGCAGATTTAATCATTGAGCGGCGAGAG GGGAGTGATGTTTGCTACCCAGGTAAGTTCGTCAATGAAGAAGCCTTGCGCCAGATCCTG CGGGAAAGCGGCGGCATTGACAAAGAGGCTATGGGATTTACTTATTCTGGCATACGAACT AACGGGGCAACGTCTGCTTGTCGACGCTCAGGCTCATCCTTCTACGCAGAAATGAAATGG TTGCTCAGTAATACAGATAATGCCGCATTTCCCCAAATGACCAAGAGCTACAAGAATACA CGGAAGAGCCCAGCCCTGATTGTGTGGGGTATCCACCATTCTGTAAGTACAGCAGAGCAG ACAAAACTGTATGGGTCTGGCAACAAACTGGTGACGGTGGGCAGTAGCAACTACCAACAG AGTTTCGTGCCGTCACCTGGGGCAAGACCCCAGGTTAACGGGCAGTCCGGCCGCATAGAC TTTCACTGGCTCATGCTGAATCCGAACGATACAGTGACTTTTTCATTCAATGGTGCATTT ATCGCCCCCGATCGCGCTTCGTTCCTCCGCGGCAAATCTATGGGAATTCAATCCGGGGTA CAGGTCGACGCCAACTGCGAGGGCGACTGTTACCATTCCGGCGGGACTATTATAAGTAAT CTACCTTTTCAGAACATAGATTCCAGAGCCGTGGGAAAATGCCCTCGCTACGTGAAACAG AGGTCCCTGCTTCTGGCTACTGGAATGAAGAATGTTCCAGAGATACCTAAGGGACGGGGC CTTTTCGGGGCAATCGCCGGATTCATCGAAAATGGGTGGGAAGGGCTGATCGATGGCTGG GTCATGGGACTCGTCTTTATCTGCGTCAAAAATGGTAACATGAGATGCACAATTTGTATC 670 ATGAATACCCAGATTTTAGTGTTTGCCCTGATTGCCATAATCCCAACTAACGCCGATAAG ATTTGCTTGGGCCACCACGCTGTGAGCAACGGCACCAAAGTCAACACCCTGACCGAACGC GGCGTGGAGGTCGTCAATGCCACCGAAACCGTGGAGCGAACCAACATTCCACGCATCTGT TCCAAGGGAAAAAGAACGGTTGATCTCGGCCAGTGTGGCCTGCTCGGGACAATCACCGGG CCGCCGCAGTGCGACCAGTTCCTGGAGTTTAGCGCCGACCTAATCATCGAACGCCGGGAG GGTTCTGATGTGTGCTACCCTGGCAAATTTGTGAATGAGGAGGCGCTTAGGCAGATTCTC AGGGAGTCCGGTGGAATTGACAAGGAAGCCATGGGTTTCACATACAGCGGTATTAGGACT AATGGCGCAACATCAGCTTGTCGAAGATCTGGTTCTAGCTTTTACGCAGAGATGAAATGG CTTCTATCCAATACTGATAATGCAGCTTTTCCCCAAATTACAAAGTCATATAAAAACACC CGCAAATCGCCCGCTCTCATAGTGTGGGGAATTCACCATTCCGTTAGTACCGCTGAACAG ACCAAATTGTATGGGAGCGGTAACAAGCTGGTCACCGTTGGGTCCTCCAATTATCAGCAG TCGTTCGTGCCGAGTCCTGGAGCCCGCCCCCAGGTCAACGGCCTTTCTGGCCGGATTGAC TTTCATTGGCTGATGTTGAACCCTAACGACACAGTTACATTCTCATTTAATGGAGCCTTC ATCGCTCCGGATCGAGCCAGCTTCCTCCGTGGTAAGAGTATGGGGATCCAAAGCGGTGTT CAGGTCGATGCCAACTGCGAGGGCGATTGTTATCATTCAGGGGGTACTATAATCAGCAAC CTGCCCTTTCAAAACATAGACAGCAGGGCAGTCGGAAAATGTCCTCGATATGTCAAACAA CGGTCTCTGTTGCTGGCTACAGGGATGAAGAACGTGCCGGAGATCCCCAAAGGACGTGGA TTATTTGGGGCCATAGCCGGGTTTATTGAGAATGGATGGGAGGGCCTGATTGATGGATGG TACGGTTTTCGCCATCAGAATGCACAGGGAGAAGGAACAGCTGCCGACTACAAGTCAACG CAGAGTGCTATTGACCAGATAACTGGCAAGTTAAACCGGCTGATCGAAAAGACTAATCAA CAATTTGAGTTGATCGACAATGAGTTTAATGAAGTTGAGAAACAGATCGGCAACGTCATC AACTGGACGCGCGATAGCATTACAGAAGTCTGGTCTTATAACGCCGAGTTGCTTGTAGCA ATGGAGAACCAGCATACCATTGATCTCGCGGACAGTGAAATGGACAAGCTCTACGAGCGC GTAAAGCGACAGCTAAGAGAAAATGCAGAAGAAGATGGGACGGGATGTTTCGAAATCTTC CACAAATGCGATGACGATTGCATGGCCAGCATACGGAATAATACCTACGATCATTCCAAG TATCGGGAAGAGGCCATGCAGAACCGCATTCAGATTGATCCCGTGAAACTTTCAAGTGGC TACAAGGACGTCATCCTGTGGTTCTCTTTCGGGGCAAGTTGTTTTATTCTGCTCGCTATT GTCATGGGTCTGGTCTTTATCTGTGTCAAAAATGGCAACATGCGGTGCACAATCTGTATT 671 ATGAACACACAGATTCTAGTGTTTGCACTGATTGCTATCATTCCTACAAATGCAGACAAG ATTTGTCTGGGCCATCACGCCGTCTCGAATGGTACAAAAGTGAATACCCTGACTGAAAGA GGGGTCGAAGTGGTTAACGCAACAGAGACCGTAGAGAGAACGAATATTCCAAGAATCTGC TCTAAGGGCAAAAAAACAGTGGATCTGGGTCAGTGTGGACTGTTAGGGACAATCACAGGT CCACCACAATGCGACCAGTTCCTTGAATTCTCGGCGGATCTTATCATCGAGCGCCGAGAA GGTTCCGACGTGTGTTACCCAGGAAAATTCGTCAATGAGGAGGCTTTGAGACAGATCTTG CGCGAAAGCGGTGGCATCGACAAAGAGGCTATGGGATTCACTTACTCTGGAATACGAACT AACGGTGCCACGTCCGCTTGCCGCAGGAGTGGATCTAGCTTCTATGCAGAGATGAAGTGG CTATTGAGCAACACTGATAATGCTGCCTTCCCTCAGATGACAAAGAGCTATAAAAACACT AGAAAGAGCCCAGCATTGATCGTTTGGGGCATTCACCACAGTGTATCCACAGCAGAGCAG ACCAAACTGTATGGGAGTGGAAACAAGCTTGTTACTGTAGGGTCCAGCAACTATCAACAG AGCTTTGTTCCGTCACCAGGTGCTCGGCCCCAGGTTAATGGGCAAAGTGGGCGGATCGAC TTCCACTGGCTGATGCTCAATCCTAATGACACGGTCACATTTTCCTTTAACGGGGCCTTC ATTGCTCCGGATCGCGCCAGCTTTCTGCGTGGAAAGAGTATGGGTATTCAAAGTGGCGTT CAGGTCGACGCCAACTGCGAGGGCGACTGCTATCATAGCGGTGGAACAATCATCTCTAAC CTGCCTTTCCAGAACATCGATAGCAGAGCCGTTGGCAAGTGTCCCAGGTACGTGAAGCAG CGATCACTGTTGTTGGCTACGGGCATGAAAAACGTCCCAGAGATTCCAAAAGGGAGGGGA CTATTCGGCGCCATTGCTGGGTTCATTGAAAATGGCTGGGAGGGTCTGATTGATGGATGG TACGGGTTTAGGCACCAAAACGCCCAAGGCGAAGGGACAGCAGCTGACTATAAATCCACT CAATCTGCTATCGACCAGATCACTGGAAAACTCAACAGACTTATTGAGAAGACTAATCAG CAGTTTGAGCTCATCGACAACGAGTTTAATGAAGTGGAGAAGCAGATTGGGAACGTTATC AACTGGACGAGGGACTCAATCACGGAAGTATGGTCCTACAATGCCGAATTGCTGGTGGCC ATGGAGAACCAGCACACCATTGACCTGGCGGACTCCGAAATGGATAAACTCTACGAACGA GTGAAGAGGCAACTCCGAGAAAATGCTGAGGAAGATGGGACCGGTTGTTTCGAGATCTTT CATAAGTGTGACGATGACTGCATGGCTTCTATTAGAAACAATACTTACGATCACTCAAAA TATAGAGAAGAGGCAATGCAGAACCGCATTCAGATCGACCCGGTGAAGCTGAGCAGTGGT TATAAGGATGTCATTTTATGGTTTAGTTTTGGAGCATCTTGTTTTATTTTGCTCGCTATC GTAATGGGCCTCGTGTTTATCTGCGTGAAAAATGGTAACATGCGGTGCACGATATGCATT 672 ATGAATACGCAGATTTTGGTTTTCGCCTTGATTGCCATTATTCCTACAAACGCCGACAAG TACGGCTTTCGCCATCAGAACGCACAGGGAGAGGGTACAGCGGCTGATTACAAATCGACT CAAAGTGCTATAGATCAGATTACCGGCAAACTGAACAGGCTGATCGAGAAAACGAATCAA CAGTTCGAACTGATTGATAACGAGTTTAACGAGGTGGAAAAACAAATCGGAAACGTTATC AATTGGACGAGGGACAGCATTACCGAAGTGTGGTCGTATAATGCAGAGCTGTTAGTCGCC ATGGAGAATCAACACACCATCGATCTTGCCGACAGCGAGATGGACAAGCTTTATGAGCGC GTGAAGAGACAACTGCGAGAAAATGCCGAGGAAGATGGAACCGGATGTTTTGAGATATTC CACAAGTGCGACGATGATTGTATGGCGAGCATCCGCAACAATACCTATGATCACTCCAAA TACAGGGAAGAGGCTATGCAAAATAGAATCCAAATTGATCCCGTCAAACTGTCAAGTGGG TACAAGGATGTGATATTATGGTTTTCCTTTGGCGCCTCATGCTTTATACTGCTGGCTATC GTGATGGGCTTGGTCTTTATTTGCGTGAAGAATGGCAACATGCGGTGTACAATATGTATT 664 ATGAATACACAAATTCTGGTGTTCGCACTCATTGCTATCATACCCACTAATGCCGATAAG ATCTGTCTGGGCCACCACGCTGTTAGCAACGGGACCAAAGTTAACACCCTTACCGAGAGG GGCGTGGAGGTGGTCAACGCAACCGAAACCGTCGAACGGACAAACATCCCGAGGATCTGC AGTAAAGGAAAGAGAACAGTCGACCTCGGGCAATGTGGACTGCTGGGGACTATTACAGGG CCCCCCCAATGTGATCAGTTCCTGGAGTTTTCTGCGGATTTAATCATTGAGAGGCGGGAG GGGAGTGATGTTTGTTACCCAGGTAAGTTTGTTAATGAAGAAGCGCTGCGCCAGATACTT AGAGAGAGTGGGGGAATCGACAAGGAGGCTATGGGTTTTACCTACAGCGGCATCAGAACA AATGGCGCCACCAGCGCATGCCGCAGGAGCGGTTCCTCATTCTACGCCGAAATGAAGTGG CTCCTATCCAATACAGATAACGCCGCCTTCCCCCAGATGACAAAGTCCTACAAAAACACC CGGAAGAGCCCTGCCCTAATTGTGTGGGGTATCCACCACTCCGTGTCTACGGCCGAGCAG ACCAAGCTGTACGGAAGCGGCAACAAACTAGTGACCGTAGGATCTAGTAACTATCAGCAG AGTTTCGTACCTTCACCAGGAGCGCGGCCTCAGGTTAATGGTCTGAGCGGGAGGATCGAT TTCCATTGGCTTATGCTGAACCCCAATGACACTGTTACGTTTTCTTTCAACGGAGCATTC ATCGCTCCAGACCGCGCGAGCTTTCTCCGAGGAAAATCAATGGGGATACAGTCTGGGGTC CAAGTGGACGCTAACTGTGAGGGGGACTGTTATCACTCAGGTGGAACCATTATTTCTAAC TTGCCATTCCAGAACATAGATTCGCGAGCCGTGGGCAAATGTCCCCGTTACGTGAAACAG CGTTCCCTCCTGCTAGCCACCGGGATGAAGAACGTACCCGAAATTCCTAAAGGGAGAGGC CTCTTTGGCGCTATTGCGGGGTTTATTGAAAACGGATGGGAGGGCCTAATTGACGGCTGG TATGGGTTCAGACATCAGAATGCACAGGGTGAGGGGACAGCTGCTGACTACAAGTCCACG CAGTCTGCAATAGATCAAATAACCGGCAAACTCAACCGCTTAATCGAGAAAACGAACCAG CAGTTCGAGCTTATAGACAATGAGTTCAATGAGGTTGAAAAACAGATCGGCAACGTGATT AATTGGACTCGGGACTCTATCACCGAGGTCTGGAGCTATAACGCAGAGTTGCTGGTCGCC ATGGAGAATCAGCACACAATAGATCTTGCTGACTCGGAAATGGACAAACTTTACGAAAGG GTCAAGCGGCAGCTGAGGGAGAACGCTGAAGAAGATGGGACGGGGTGCTTCGAAATTTTT CATAAGTGCGATGATGATTGTATGGCGTCCATTAGAAATAACACCTACGACCATAGTAAA TACCGGGAGGAAGCCATGCAGAACAGGATCCAGATCGACCCAGTAAAACTGTCAAGTGGG TATAAGGATGTTATATTGTGGTTCTCGTTCGGCGCCAGTTGCTTCATCCTCCTCGCTATT GTCATGGGCCTTGTGTTTATTTGCGTGAAGAATGGAAATATGCGCTGCACCATTTGCATT 665 ATGAATACCCAGATACTGGTGTTTGCCTTAATAGCAATTATCCCAACAAATGCCGACAAG ATCTGCCTTGGACACCACGCCGTGTCCAATGGTACTAAAGTGAACACCTTGACCGAGCGG GGGGTGGAGGTGGTAAATGCCACGGAGACTGTCGAACGTACAAATATCCCCCGCATCTGT TCTAAAGGCAAAAAAACTGTCGACTTGGGCCAGTGCGGACTACTGGGGACGATTACTGGT CCGCCTCAGTGCGACCAATTCCTCGAATTTAGTGCAGATCTCATTATTGAAAGACGAGAG GGGAGTGACGTTTGCTATCCAGGCAAGTTCGTTAACGAGGAAGCCCTTAGGCAAATTTTG AGGGAGTCGGGGGGAATTGATAAAGAAGCAATGGGATTTACTTACAGCGGCATTCGGACC AACGGTGCTACCTCAGCATGCAGGCGCTCTGGCTCCTCCTTCTACGCTGAGATGAAATGG CTACTGTCCAACACCGACAATGCAGCATTTCCTCAAATGACTAAGAGCTATAAGAACACA AGAAAATCCCCCGCCCTCATAGTCTGGGGGATCCACCACTCAGTGTCCACCGCAGAGCAG ACGAAATTATATGGATCCGGAAATAAACTGGTGACAGTGGGGAGTAGTAACTACCAACAG AGTTTTGTTCCCAGCCCAGGCGCCAGACCTCAGGTAAATGGACAGTCCGGAAGGATCGAT TTTCATTGGCTCATGCTAAACCCCAACGATACCGTCACATTCTCATTCAACGGAGCATTT ATAGCTCCCGACCGGGCTTCATTCCTTCGGGGTAAATCAATGGGCATTCAGTCTGGGGTA CAAGTGGACGCCAATTGTGAGGGCGACTGCTATCACTCTGGCGGAACAATCATATCTAAT CTCCCATTCCAGAACATCGATTCCCGCGCAGTCGGCAAGTGTCCAAGGTACGTGAAACAG CGCTCCCTGTTGTTGGCAACTGGAATGAAAAATGTACCAGAGATTCCTAAGGGACGTGGA CTGTTCGGAGCTATTGCAGGGTTCATCGAAAATGGGTGGGAGGGCCTAATCGACGGTTGG TATGGGTTCAGACATCAGAACGCCCAGGGGGAGGGTACTGCCGCCGATTACAAGTCCACC CAGTCCGCAATTGACCAGATCACGGGTAAATTAAACAGACTCATTGAAAAAACTAATCAG CAGTTCGAGCTTATTGATAATGAATTTAATGAAGTGGAAAAGCAGATAGGGAATGTGATT AACTGGACCCGCGACTCTATCACAGAAGTCTGGTCATACAATGCTGAACTGCTTGTCGCC ATGGAAAATCAGCATACCATAGACCTTGCAGATTCAGAAATGGACAAGCTGTACGAAAGA GTCAAAAGACAGCTGAGGGAGAATGCCGAGGAGGATGGTACAGGGTGCTTCGAAATCTTC CACAAGTGCGACGATGACTGTATGGCGAGCATCCGCAATAATACGTATGACCATTCTAAA TACAGAGAAGAGGCGATGCAGAATCGGATCCAAATCGACCCGGTAAAGCTCAGTTCGGGC TACAAAGACGTAATACTATGGTTCTCCTTTGGAGCTTCGTGCTTCATTCTCCTAGCTATC GTCATGGGGTTAGTCTTCATCTGCGTGAAGAATGGTAATATGCGCTGTACAATTTGTATA 666 ATGAACACACAGATCCTAGTGTTTGCCCTCATCGCCATTATTCCAACAAACGCTGATAAG ATTTGCCTAGGACATCACGCAGTGTCCAACGGAACTAAGGTGAACACCTTAACTGAGAGG GGAGTAGAGGTGGTGAATGCCACAGAGACTGTTGAAAGAACCAATATTCCCCGTATCTGC TCAAAGGGGAAGAGAACGGTAGACCTGGGGCAGTGTGGCTTGCTGGGCACCATCACCGGC CCACCCCAGTGCGATCAGTTTTTGGAATTCTCTGCCGATTTAATAATAGAACGCAGAGAA GGTTCCGACGTGTGCTACCCTGGAAAATTCGTCAATGAGGAAGCACTGAGGCAGATCTTA CGCGAGTCCGGAGGCATCGACAAAGAGGCAATGGGATTCACTTACTCCGGAATCCGGACT AACGGGGCGACGAGCGCCTGCAGGCGTAGCGGCTCCTCTTTTTACGCGGAAATGAAGTGG CTTCTATCCAACACTGACAATGCCGCTTTTCCACAAATGACCAAGTCTTATAAAAACACA CGCAAGTCGCCCGCCTTAATAGTGTGGGGCATTCATCATTCCGTGTCAACAGCAGAGCAG ACTAAGTTGTATGGCAGTGGTTCTAAGTTGGTGACAGTAGGATCCTCCAACTACCAGCAA AGTTTCGTGCCTAGCCCAGGCGCACGTCCCCAGGTGAACGGCCTTTCAGGGAGGATCGAT TTCCATTGGCTGATGCTCAACCCCAACGACACTGTTACTTTCTCCTTCAACGGAGCATTT ATCGCACCAGATCGGGCCTCCTTCTTGCGGGGAAAATCTATGGGAATCCAGAGCGGAGTG CAGGTGGATGCCAATTGTGAAGGGGATTGCTACCACTCTGGGGGAACAATTATCTCCAAT TTGCCCTTCCAGAATATCGATTCCCGAGCTGTCGGAAAATGTCCGAGGTATGTCAAGCAG CGTAGTCTGCTCCTTGCCACGGGCATGAAGAACGTCCCAGAGATTCCCAAGGGCCGGGGC TTATTCGGGGCTATCGCCGGGTTCATCGAGAACGGATGGGAGGGGCTAATAGACGGCTGG TATGGCTTCAGGCATCAGAATGCACAAGGTGAAGGAACGGCGGCTGATTATAAATCCACC CAGAGTGCCATCGATCAGATTACAGGTAAGCTTAACCGGCTAATCGAAAAGACGAATCAG CAGTTTGAACTCATCGATAACGAGTTCAATGAGGTGGAGAAGCAGATCGGAAATGTCATC AACTGGACTCGAGACTCGATCACTGAGGTGTGGTCCTACAATGCTGAGCTTCTGGTCGCT ATGGAAAATCAACACACCATCGATCTGGCAGACTCAGAAATGGACAAGTTGTACGAGCGG GTGAAGAGACAACTAAGGGAAAACGCCGAGGAAGATGGCACTGGATGCTTTGAAATCTTT CACAAGTGCGACGATGACTGCATGGCTTCAATCAGAAATAACACCTACGATCACAGCAAG TACAGAGAAGAAGCAATGCAGAACCGTATTCAAATCGACCCCGTCAAGCTGTCCAGCGGA TACAAGGATGTGATCCTGTGGTTCTCCTTCGGGGCAAGCTGTTTCATCCTGCTGGCTATA GTGATGGGCCTGGTCTTCATTTGTGTCAAGTCCAGGAATATGCGGTGTACTATCTGTATT 667 ATGAACACCCAGATACTGGTCTTTGCTCTCATAGCGATCATACCAACCAACGCTGACAAA ATCTGTCTGGGGCACCACGCGGTGTCTAACGGCACTAAGGTAAACACCCTCACTGAACGC GGTGTGGAGGTGGTGAACGCCACCGAGACCGTTGAGCGTACAAATATACCCAGGATCTGT TCCAAGGGTAAAAGGACCGTCGACCTTGGCCAGTGTGGCCTGCTGGGCACCATTACGGGC CCTCCCCAATGCGATCAATTTCTTGAGTTCAGCGCCGATTTGATCATAGAGCGACGTGAG GGGTCAGACGTGTGTTACCCTGGGAAATTTGTGAAGGAAGAAGCACTGCGACAGATCCTT CGAGAGTCTGGAGGGATTGATAAGGAAGCTATGGGCTTCACCTATAGCGGAATCAGGACT AACGGCGCTACTAGTGCGTGCAGACGATCTGGAAGCAGTTTTTACGCCGAAATGAAGTGG CTGCTGTCTAATACTGATAATGCCGCCTTCCCACAAATGACCAAGTCCTACAAGAACACA CGGAAGTCCCCAGCTCTGATCGTGTGGGGCATCCATCACTCGGTCTCCACAGCCGAGCAA ACAAAGCTTTACGGGTCAGGAAACAAATTGGTAACCGTGGGCTCTAGTAACTATCAACAG AGCTTCGTCCCGTCCCCCGGTGCACGCCCACAGGTGAACGGTTTAAGTGGGCGCATCGAC TTCCATTGGCTCATGCTGAACCCTAATGACACAGTGACCTTTTCCTTTAACGGGGCATTC ATCGCCCCTGATAGGGCATCCTTCCTCCGGGGCAAGAGTATGGGGATACAATCGGGGGTG CAAGTCGACGCAAATTGCGAGGGTGATTGTTACCACTCTGGGGGTACCATCATTTCCAAC CTGCCCTTTCAGAACATAGATTCGAGGGCTGTCGGGAAGTGCCCTCGATATGTGAAGCAG CGGAGTCTCCTGCTGGCAACAGGCATGAAGAACGTCCCCGAGATCCCCAAAGGACGAGGA CTCTTCGGCGCAATCGCCGGTTTTATAGAGAACGGATGGGAAGGCCTGATCGACGGTTGG TATGGCTTTCGTCACCAGAACGCGCAGGGTGAGGGCACTGCCGCCGACTATAAGAGCACA CAGTCCGCCATCGACCAAATTACTGGAAAGCTTAATAGACTAATCGAAAAAACAAACCAA CAGTTTGAGCTGATTGACAATGAGTTTAATGAGGTGGAGAAGCAGATAGGTAATGTGATA AATTGGACCCGGGATTCTATTACCGAAGTGTGGTCATACAATGCGGAACTGCTGGTAGCA ATGGAAAATCAGCACACAATCGATCTGGCCGATAGTGAGATGGACAAGTTGTACGAGAGG GTTAAGAGGCAGCTTCGGGAAAATGCAGAAGAGGATGGTACCGGGTGTTTTGAAATCTTC CACAAGTGCGATGACGACTGCATGGCTTCTATCAGAAACAATACATACGACCACAGCAAA TATCGGGAGGAAGCCATGCAGAACCGAATCCAGATCGATCCCGTCAAGCTTAGCTCGGGC TATAAAGATGTCATTCTGTGGTTTTCCTTTGGAGCCTCCTGTTTCATCCTCCTAGCCATT GTGATGGGTCTTGTGTTTATCTGCGTGAAGAACGGCAATATGAGGTGCACTATCTGCATT 668 ATGAATACCCAAATTCTTGTGTTCGCCCTGATCGCTATTATCCCGACGAACGCCGATAAG ATCTGCCTAGGACACCACGCTGTGAGTAATGGAACCAAGGTGAACACACTGACTGAGAGG GGCGTGGAGGTGGTGAACGCGACAGAGACCGTGGAACGAACAAATATTCCGAGGATCTGT TCAAAGGGGAAGAGAACCGTGGATCTGGGCCAGTGCGGACTGCTAGGCACTATTACCGGC CCACCACAGTGTGACCAGTTCCTGGAGTTTAGTGCCGACCTGATTATTGAAAGGCGCGAG GGAAGTGACGTTTGTTACCCCGGGAAATTCGTAAATGAGGAGGCCCTCAGACAAATACTA AGAGAGTCCGGCGGAATTGACAAAGAGGCGATGGGCTTTACATACAGCGGTATAAGAACG AACGGGGCGACCTCCGCATGTAGGCGTAGTGGCTCAAGTTTCTATGCCGAGATGAAGTGG CTGCTGAGCAATACAGACAATGCCGCCTTTCCCCAGATGACCAAGTCTTACAAGAATACG AGAAAAAGTCCAGCACTCATTGTGTGGGGTATCCATCATTCTGTGAGCACAGCAGAACAA ACAAAGCTGTACGGCTCAGGAAACAAGCTCGTGACTGTGGGCAGCTCTAACTACCAGCAA TCATTCGTCCCCTCCCCGGGAGCCAGACCACAGGTTAACGGACTGAGTGGGCGAATTGAT TTCCACTGGCTTATGTTAAACCCCAATGATACTGTGACATTTTCTTTCAACGGCGCGTTT ATCGCTCCAGATCGTGCCAGTTTTCTGAGGGGGAAGTCCATGGGCATCCAGTCCGGAGTG CAGGTTGACGCCAATTGTGAAGGGGACTGTTACCATTCTGGTGGGACTATTATTTCGAAC CTACCCTTCCAGAATATTGACAGCCGGGCCGTTGGTAAATGCCCTCGGTACGTTAAACAA AGAAGCCTCCTGCTGGCGACCGGAATGAAGAATGTGCCTGAAATTCCGAAAGGACGCGGA CTGTTCGGCGCTATCGCAGGGTTTATAGAAAACGGTTGGGAGGGCTTAATTAACGGTTGG TATGGCTTTCGGCACCAGAACGCCCAGGGCGAGGGGACCGCCGCCGACTATAAAAGCACA CAGTCTGCGATTGATCAGATTACCGGGAAGCTCAACAGGCTCATAGAGAAAACAAACCAA CAGTTTGAACTGATTGACAATGAATTTAACGAGGTAGAAAAACAGATTGGCAATGTTATC AACTGGACCAGGGATTCAATTACAGAGGTGTGGTCTTATAATGCCGAGCTATTGGTGGCC ATGGAAAACCAACATACAATCGACCTCGCCGATTCAGAGATGGACAAGCTGTATGAGAGG GTCAAAAGACAGTTGCGCGAGAATGCCGAGGAGGACGGGACTGGCTGCTTCGAGATCTTT CACAAATGCGATGACGACTGTATGGCTAGTATCCGCAACAACACGTATGATCACTCTAAG TACCGCGAGGAAGCCATGCAGAATCGGATCCAAATTGATCCAGTTAAACTGTCTAGCGGC TACAAGGATGTGATTCTGTGGTTTTCTTTCGGAGCATCCTGCTTCATCTTGTTAGCCATT GTGATGGGCCTGGTTTTTATCTGCGTGAAGAACGGCAATATGCGGTGTACTATCTGCATC 669 ATGAATACGCAGATTCTGGTGTTTGCCTTAATAGCTATTATCCCCACTAATGCCGACAAG ATCTGTTTAGGGCACCACGCTGTATCAAATGGCACCAAAGTCAATACGCTCACCGAACGG GGGGTGGAAGTTGTGAACGCGACTGAAACTGTCGAAAGAACCAATATTCCGCGAATTTGC AGTAAGGGAAAGAAGACTGTGGACCTGGGCCAATGTGGCTTGTTGGGCACCATTACCGGT CCACCGCAGTGCGATCAATTTCTTGAATTCTCTGCAGACCTGATAATCGAACGCCGCGAG GGCTCTGACGTGTGTTATCCTGGGAAATTTGTTAATGAGGAAGCCCTCAGGCAGATACTC AGGGAATCTGGCGGTATTGATAAGGAGGCCATGGGGTTCACGTACTCTGGTATACGCACC AATGGTGCCACATCCGCATGCAGGAGAAGCGGCTCCTCGTTCTATGCAGAAATGAAGTGG TTGCTGTCGAACACAGACAACGCCGCCTTTCCACAGATGACAAAGAGTTACAAGAACACA AGGAAGTCACCTGCCCTGATCGTTTGGGGTATTCATCATTCTGTCTCCACAGCTGAGCAG ACCAAACTGTACGGGTCAGGAAACAAGCTGGTGACTGTGGGTTCCTCGAATTATCAGCAG AGCTTTGTTCCGTCCCCAGGTGCGAGGCCCCAGGTGAACGGCCAATCCGGGCGCATCGAC TTTCACTGGCTGATGCTTAACCCAAACGATACTGTGACCTTCTCCTTTAACGGAGCGTTT ATCGCTCCAGACAGGGCCTCGTTTCTGAGAGGGAAAAGCATGGGAATCCAGTCAGGGGTG CAGGTGGATGCTAATTGTGAAGGTGACTGTTACCACTCAGGAGGCACAATCATTAGCAAC CTGCCCTTTCAGAACATTGACTCCAGGGCAGTGGGCAAATGTCCACGGTATGTGAAGCAG AGAAGCCTCCTCCTGGCCACAGGCATGAAGAACGTGCCAGAGATTCCCAAGGGTAGGGGC CTGTTCGGTGCTATAGCCGGATTTATTGAGAATGGATGGGAAGGGCTGATCGACGGTTGG TACGGCTTTAGACACCAGAACGCTCAGGGAGAGGGAACTGCCGCAGACTATAAAAGTACT CAAAGCGCGATCGACCAGATAACAGGTAAGCTCAACCGTCTCATTGAGAAAACAAACCAG CAGTTCGAACTCATCGATAACGAGTTTAACGAAGTCGAGAAACAAATTGGAAACGTCATT AACTGGACTAGAGATTCAATCACTGAGGTGTGGAGCTACAACGCTGAGCTGCTTGTGGCT ATGGAGAATCAGCATACCATAGATCTGGCTGACTCTGAAATGGATAAACTCTATGAACGA GTCAAGAGACAGCTCAGGGAGAATGCTGAAGAGGATGGCACAGGATGTTTCGAAATCTTC CACAAGTGTGACGACGACTGCATGGCAAGCATTAGGAATAACACATATGATCATTCTAAA TATAGGGAAGAGGCAATGCAGAATCGGATCCAAATTGATCCAGTCAAGTTATCTTCCGGG TATAAAGACGTGATCCTTTGGTTCAGCTTTGGCGCTTCATGTTTCATCTTGCTTGCCATC ATCTGCCTGGGACATCACGCCGTGAGTAATGGAACCAAGGTGAATACACTGACCGAGAGG GGCGTAGAAGTTGTAAATGCTACTGAGACAGTGGAGCGAACAAATATTCCCAGAATTTGC TCCAAGGGCAAGAAGACTGTCGACCTTGGCCAATGTGGGCTGCTCGGCACGATCACGGGG CCACCCCAATGTGATCAGTTTCTGGAGTTTTCTGCCGACCTCATTATAGAACGCCGGGAG GGGAGCGACGTATGCTACCCCGGTAAGTTCGTAAACGAAGAAGCCCTCAGACAGATTTTG AGGGAGTCCGGAGGCATCGATAAGGAGGCAATGGGCTTCACCTACAGCGGCATCAGAACA AACGGTGCCACAAGTGCATGTAGGCGCTCTGGCTCATCATTCTATGCAGAGATGAAGTGG CTGCTTTCCAATACTGATAATGCGGCCTTTCCTCAGATGACTAAATCATATAAGAACACC AGAAAATCTCCCGCCTTGATCGTCTGGGGGATCCATCACAGCGTCTCTACCGCTGAGCAG ACCAAACTCTACGGTTCAGGGAACAAATTAGTGACCGTTGGCAGCTCCAACTACCAGCAA TCATTTGTGCCTTCCCCAGGTGCCAGGCCGCAAGTAAACGGTCAGTCAGGACGAATTGAT TTCCACTGGCTAATGCTGAACCCGAATGACACAGTCACCTTCAGCTTTAACGGGGCTTTC ATCGCACCCGACCGCGCCAGTTTCTTACGGGGAAAATCAATGGGAATACAATCCGGCGTT CAAGTGGACGCGAATTGCGAGGGAGATTGTTACCATAGTGGTGGTACAATTATCTCCAAT CTTCCCTTTCAGAATATCGACAGTAGGGCAGTGGGAAAATGTCCCCGATACGTCAAACAG CGGAGCCTGCTCCTCGCCACCGGGATGAAGAACGTCCCCGAGATTCCAAAAGGTAGGGGT TTGTTCGGAGCTATCGCAGGGTTCATCGAAAACGGCTGGGAAGGCCTGATAGACGGTTGG TATGGATTCCGACACCAAAACGCTCAAGGCGAGGGCACTGCAGCAGATTACAAATCTACA CAAAGCGCTATCGACCAGATTACCGGAAAACTTAACCGTCTAATCGAAAAGACCAATCAG CAGTTCGAGCTCATCGATAACGAATTCAATGAGGTGGAGAAACAGATCGGAAACGTAATC AATTGGACACGAGATTCCATCACTGAGGTTTGGTCTTATAACGCCGAACTCTTAGTGGCT ATGGAGAATCAGCACACCATCGACCTGGCTGATTCCGAGATGGACAAGCTGTACGAAAGA GTGAAGAGACAGCTTCGCGAAAACGCAGAGGAGGATGGGACCGGATGTTTCGAAATCTTC CACAAATGTGATGATGATTGCATGGCCAGCATCCGGAACAACACATATGATCATTCGAAA TATCGCGAGGAGGCTATGCAAAATCGGATCCAGATCGATCCCGTCAAGCTAAGCTCTGGG TACAAGGACGTGATTTTATGGTTTTCCTTCGGCGCTTCATGTTTCATCCTTCTGGCCATC GTGATGGGCCTAGTGTTTATCTGCGTCAAGAATGGAAACATGAGATGTACGATCTGCATC 673 ATGAACACTCAGATTCTGGTATTTGCGCTAATCGCAATCATTCCCACCAACGCAGACAAG ATTTGTCTGGGACATCATGCCGTGAGCAACGGCACAAAAGTGAACACTCTGACTGAAAGG GGAGTGGAGGTTGTAAATGCGACCGAAACTGTGGAAAGAACCAATATACCCCGAATCTGT AGCAAGGGTAAAAAGACCGTAGACTTAGGACAGTGTGGTCTCTTGGGGACAATCACAGGC CCCCCTCAATGTGACCAGTTCTTAGAGTTTAGCGCAGATTTGATTATCGAGCGAAGGGAG GGAAGTGACGTTTGTTACCCTGGGAAGTTCGTGAATGAAGAAGCTCTCCGTCAGATCTTG AGGGAGTCCGGAGGCATAGACAAAGAGGCCATGGGGTTCACTTACTCCGGGATTCGCACA AATGGAGCTACAAGTGCCTGTAGAAGGTCAGGCAGTTCTTTCTATGCTGAGATGAAATGG CTCTTATCAAACACAGACAACGCTGCCTTCCCACAGATGACAAAATCCTACAAAAACACT CGCAAATCCCCAGCCCTTATCGTGTGGGGGATCCATCACTCCGTGTCCACTGCGGAACAG ACTAAGCTGTATGGATCCGGGAACAAACTGGTAACTGTAGGGAGTAGCAACTACCAGCAG TCCTTCGTCCCATCTCCTGGGGCACGCCCCCAGGTAAACGGACAGTCTGGAAGAATTGAT TTCCACTGGTTGATGCTGAACCCAAATGATACTGTGACCTTCTCTTTCAATGGCGCTTTC ATCGCGCCCGATCGCGCTAGCTTCCTAAGGGGAAAATCCATGGGGATTCAGTCTGGCGTC CAGGTCGATGCAAATTGCGAAGGCGACTGTTACCATTCTGGAGGGACCATTATCAGTAAC CTGCCATTCCAGAATATTGACTCGAGGGCAGTGGGTAAGTGCCCCAGGTACGTGAAACAA AGATCACTGCTTCTGGCTACAGGAATGAAGAACGTACCTGAGATCCCTAAAGGGCGGGGA TTATTCGGAGCCATCGCAGGCTTCATAGAGAACGGGTGGGAGGGCCTGATTGATGGGTGG TACGGATTCAGGCACCAAAATGCCCAGGGAGAAGGGACCGCTGCGGATTACAAGAGTACC CAGTCCGCTATAGACCAGATCACAGGCAAACTTAATAGGCTGATTGAAAAGACCAATCAG CAGTTTGAACTCATCGATAACGAATTTAACGAGGTGGAAAAGCAGATTGGGAACGTGATT AACTGGACAAGGGATTCTATTACCGAGGTGTGGAGCTACAATGCCGAGCTGTTGGTTGCG ATGGAGAATCAGCACACTATCGATCTAGCAGACTCCGAAATGGACAAGTTGTATGAAAGA GTGAAGCGCCAATTAAGGGAAAACGCAGAGGAGGATGGGACCGGATGTTTTGAGATCTTC CATAAATGCGATGACGACTGCATGGCCAGCATTAGAAATAATACCTACGACCATAGTAAG TATAGGGAGGAGGCGATGCAAAACAGAATTCAAATAGACCCAGTGAAACTGAGTTCTGGG TACAAAGACGTTATTCTCTGGTTTTCATTCGGCGCCAGCTGCTTTATACTGCTGGCTATC GTCATGGGCTTGGTCTTCATCTGCGTGAAAAACGGGAATATGCGATGCACAATTTGTATT 674 ATGAATACCCAGATCCTGGTGTTCGCTCTCATCGCCATCATACCAACAAACGCTGACAAG ATCTGCCTAGGTCACCACGCTGTGTCTAATGGAACCAAAGTGAATACACTGACCGAGCGC GGTGTGGAGGTGGTGAACGCTACAGAGACCGTGGAACGCACTAATATCCCTCGAATATGT TCTAAGGGCAAGAAAACTGTAGATCTGGGGCAGTGCGGCCTTCTGGGAACTATCACGGGC CCTCCACAGTGCGATCAATTTTTGGAGTTTTCTGCCGACCTCATCATCGAACGCCGTGAG GGATCGGACGTGTGTTATCCAGGAAAGTTTGTGAATGAGGAAGCGCTCCGGCAGATCTTA AGAGAAAGCGGTGGTATTGACAAAGAAGCAATGGGCTTCACCTATTCAGGAATTAGGACC AACGGAGCAACCAGTGCGTGTAGACGAAGCGGGTCTTCATTCTACGCCGAAATGAAGTGG CTGCTTTCTAACACCGATAACGCAGCATTCCCACAAATGACCAAGAGCTACAAGAATACA AGAAAATCCCCTGCATTAATTGTATGGGGAATCCATCACTCCGTCTCAACAGCAGAACAG ACAAAACTTTATGGCAGTGGCAACAAACTCGTCACCGTTGGTAGCTCCAACTACCAGCAG TCTTTCGTGCCAAGTCCCGGGGCCCGACCGCAAGTGAACGGGCAGTCTGGCAGAATCGAC TTTCACTGGCTCATGCTGAATCCAAACGACACAGTTACCTTCAGCTTCAATGGGGCATTC ATTGCCCCAGACAGAGCCAGCTTTCTTCGAGGCAAGAGCATGGGCATCCAGAGCGGGGTA CAGGTCGACGCAAACTGTGAAGGAGATTGCTACCACTCCGGCGGGACGATCATTTCGAAT CTGCCATTCCAGAATATCGACTCTAGGGCTGTGGGGAAATGTCCTAGGTATGTGAAACAG CGGAGCCTCCTTCTGGCAACAGGAATGAAAAACGTACCTGAGATCCCTAAGGGGCGAGGA TTGTTTGGTGCCATCGCGGGATTCATTGAAAATGGCTGGGAGGGATTGATTGACGGCTGG TACGGATTCCGGCATCAAAACGCGCAAGGGGAGGGTACGGCGGCAGATTACAAAAGCACT CAGTCCGCGATCGACCAGATCACCGGCAAACTCAATAGACTTATCGAGAAGACTAACCAA CAGTTCGAGCTCATCGACAATGAGTTTAATGAAGTAGAGAAACAGATCGGCAATGTCATA AACTGGACCAGGGACAGCATCACCGAAGTGTGGTCCTATAACGCCGAGCTCCTGGTGGCC ATGGAGAATCAGCACACTATAGACTTAGCTGACTCTGAGATGGACAAGCTCTATGAGAGA GTTAAACGGCAGCTCAGAGAAAACGCAGAAGAAGATGGCACCGGGTGCTTCGAGATCTTT CATAAATGTGATGACGACTGCATGGCCTCGATACGTAACAATACATATGATCATAGTAAG TATCGGGAGGAAGCAATGCAGAACAGGATTCAGATCGACCCCGTTAAATTGTCCAGCGGC TATAAGGACGTAATTCTGTGGTTCTCGTTTGGCGCCTCCTGTTTCATTTTGTTGGCCATT GTGATGGGTCTCGTCTTCATTTGCGTAAAAAATGGCAATATGCGGTGCACTATTTGTATC 675 ATGAATACTCAGATCCTAGTTTTTGCTCTGATTGCCATAATTCCGACGAATGCGGACAAG ATTTGCCTGGGACACCACGCTGTCAGTAACGGTACCAAAGTAAATACCCTGACGGAGCGA GGTGTCGAGGTGGTGAATGCCACCGAAACTGTGGAGAGAACCAACATCCCTCGGATCTGT AGCAAGGGCAAGAAAACTGTGGACCTCGGTCAGTGTGGGTTGCTCGGGACCATTACAGGC CCCCCACAGTGCGATCAATTTCTGGAGTTCTCTGCCGACTTAATTATTGAAAGACGGGAG GGTAGCGACGTTTGTTATCCCGGCAAATTCGTAAATGAGGAGGCCTTGCGCCAGATTTTG CGCGAGTCCGGCGGCATTGATAAAGAGGCTATGGGATTCACTTATTCTGGCATTAGGACA AACGGCGCGACCAGTGCATGTCGCCGATCCGGCTCCTCCTTTTACGCTGAGATGAAATGG CTGTTGTCGAACACTGACAACGCTGCATTTCCACAGATGACAAAGTCCTATAAGAACACC AGGAAGAGTCCGGCCCTGATCGTGTGGGGAATACATCACTCTGTGTCCACCGCCGAACAG ACCAAGCTGTACGGAAGTGGCAATAAGCTGGTTACTGTCGGGAGCAGCAATTACCAGCAG AGTTTTGTGCCGTCACCCGGGGCCCGGCCTCAGGTGAATGGTCAGTCCGGTAGAATAGAC TTCCACTGGCTTATGCTAAACCCAAATGACACCGTTACCTTCTCATTTAACGGTGCCTTT ATTGCCCCCGACCGGGCTTCATTCCTGCGCGGGAAATCCATGGGCATCCAATCTGGGGTG CAGGTTGACGCTAATTGTGAGGGAGACTGTTATCATAGCGGAGGCACCATAATCTCCAAT CTGCCCTTCCAGAACATTGACAGCAGAGCAGTAGGCAAATGCCCCAGGTATGTCAAGCAA CGAAGCCTTCTTCTCGCTACCGGTATGAAGAATGTGCCCGAAATACCAAAGGGACGGGGG CTCTTTGGCGCGATAGCCGGGTTCATCGAGAATGGATGGGAGGGACTCATTGACGGTTGG TATGGGTTCCGCCATCAGAACGCGCAGGGGGAAGGCACAGCAGCCGACTATAAGTCCACA CAGAGTGCAATTGACCAAATTACCGGCAAATTAAACAGACTCATTGAGAAGACTAACCAG CAGTTTGAGTTAATTGATAATGAGTTTAACGAAGTGGAGAAACAAATTGGAAACGTGATC AACTGGACACGAGATAGCATTACGGAGGTATGGTCATATAACGCCGAGCTGCTCGTTGCG ATGGAGAATCAACACACAATTGATTTAGCAGACTCCGAAATGGACAAACTTTACGAACGG GTGAAACGCCAGCTGCGCGAAAACGCTGAAGAAGATGGGACAGGTTGCTTTGAAATTTTT CACAAGTGCGATGATGACTGCATGGCCTCAATCCGTAATAATACATACGATCACAGCAAG TATAGGGAAGAAGCCATGCAGAATAGGATTCAAATAGACCCGGTGAAATTATCTTCTGGC TATAAAGATGTTATTCTGTGGTTCTCCTTCGGCGCGTCATGTTTCATTTTATTGGCCATT GTGATGGGCCTGGTTTTCATATGCGTGAAGAACGGAAATATGAGATGCACCATCTGTATT 676 ATGAACACACAAATCCTGGTGTTTGCCTTAATAGCTATTATCCCAACCAACGCAGACAAG ATCTGTCTTGGACACCATGCTGTAAGCAATGGAACCAAAGTGAACACATTGACCGAGCGT GGGGTCGAAGTGGTTAACGCCACCGAGACAGTGGAGAGGACTAATATCCCCAGAATTTGT AGTAAAGGGAAGAGGACAGTTGACTTAGGACAATGCGGACTGTTGGGTACCATTACAGGT CCACCCCAGTGTGATCAGTTTCTGGAATTCAGCGCTGATTTGATCATCGAGCGGAGAGAA GGCAGTGATGTCTGTTACCCTGGGAAATTCGTCAACGAAGAGGCATTGCGCCAGATTTTG AGGGAATCCGGCGGAATCGACAAAGAAGCCATGGGGTTCACATACTCAGGGATCCGGACG AATGGCGCAACGAGCGCTTGTAGGAGGTCCGGGAGTTCTTTCTATGCGGAGATGAAATGG CTATTGAGCAACACAGATAATGCCGCTTTCCCTCAAATGACCAAGTCATACAAAAATACA AGGAAGAGCCCAGCCCTTATCGTGTGGGGTATCCATCACAGTGTGTCTACCGCAGAACAG ACAAAACTCTACGGCAGCGGGAACAAACTTGTGACCGTCGGCTCTTCAAACTATCAACAG AGTTTCGTTCCGTCTCCAGGCGCAAGGCCACAGGTGAATGGATTAAGTGGGCGGATCGAT TTTCATTGGCTTATGCTCAACCCTAATGATACAGTCACATTCTCTTTTAATGGAGCTTTC ATTGCCCCAGACAGGGCGTCCTTCCTGCGAGGCAAATCTATGGGTATACAAAGCGGCGTC CAGGTAGACGCAAATTGTGAGGGTGATTGCTACCACAGCGGGGGAACCATTATCAGCAAC TTGCCATTCCAAAACATCGATTCCCGTGCTGTGGGCAAGTGTCCAAGATATGTGAAACAG AGGAGTCTGTTGTTGGCGACGGGAATGAAAAACGTTCCCGAGATTCCAAAGGGCCGGGGA CTTTTTGGGGCCATCGCCGGATTCATAGAGAACGGCTGGGAAGGACTCATTAATGGATGG TATGGGTTCCGGCATCAGAACGCTCAGGGGGAGGGCACCGCTGCTGACTACAAGAGTACC CAGTCTGCCATCGATCAGATTACCGGTAAGTTGAATAGGCTGATCGAGAAAACTAACCAG CAGTTTGAGCTCATTGATAATGAATTCAACGAGGTAGAAAAACAGATAGGCAACGTGATT AACTGGACCCGTGACTCCATAACGGAGGTATGGAGTTATAATGCAGAACTCCTCGTGGCT ATGGAAAATCAGCACACAATTGATTTAGCTGACTCAGAAATGGATAAGCTGTACGAGCGG GTCAAACGCCAACTGCGCGAGAATGCAGAAGAAGACGGGACCGGGTGTTTCGAAATCTTT CATAAATGCGACGATGACTGTATGGCCAGCATCCGTAACAACACTTACGACCACAGCAAG TATCGGGAGGAAGCTATGCAAAATAGGATCCAGATCGACCCTGTCAAATTATCCAGTGGG TACAAAGATGTCATCCTGTGGTTTTCCTTTGGCGCGTCATGCTTTATTTTGTTGGCTATC GTGATGGGCCTCGTTTTTATCTGTGTGAAGAATGGAAACATGCGATGCACCATCTGTATT 677 ATGAACACTCAGATTCTGGTGTTCGCACTAATCGCAATCATACCTACTAATGCCGACAAA ATTTGCCTCGGCCACCATGCCGTGTCAAATGGCACAAAAGTGAATACCCTGACGGAGCGC GGCGTCGAGGTTGTCAATGCCACAGAGACAGTGGAACGGACCAACATTCCACGTATTTGT TCAAAAGGCAAGCGTACCGTTGACCTGGGTCAGTGCGGACTTCTCGGGACAATCACTGGA CCACCACAGTGCGATCAGTTCTTGGAGTTTTCAGCAGACCTTATCATCGAGAGGCGGGAA GGTAGCGACGTTTGCTACCCCGGCAAATTTGTTAATGAAGAAGCCTTAAGGCAGATCCTA CGAGAATCAGGGGGCATTGACAAAGAAGCGATGGGATTCACTTACAGTGGAATTAGAACA AACGGTGCCACGTCTGCTTGCAGACGCTCGGGCTCTAGCTTTTATGCTGAAATGAAATGG TTGCTGAGCAATACCGATAATGCTGCCTTCCCACAGATGACAAAAAGTTACAAGAATACT AGAAAGTCACCCGCACTGATCGTCTGGGGGATTCACCATTCAGTCAGCACCGCCGAGCAG ACCAAACTTTATGGTAGCGGTAACAAGTTAGTGACAGTTGGAAGCTCCAATTATCAACAG TCATTTGTGCCATCTCCCGGGGCTCGACCCCAAGTGAACGGGTTAAGTGGTCGGATCGAC TTCCACTGGTTGATGCTCAACCCTAACGACACAGTCACATTCTCCTTCAACGGCGCATTC ATAGCCCCCGACCGGGCAAGCTTCCTAAGGGGAAAGAGTATGGGAATCCAGTCTGGGGTG CAAGTTGATGCCAACTGCGAAGGGGATTGCTATCATTCCGGCGGGACAATTATAAGCAAC CTGCCATTCCAGAACATCGATTCACGGGCAGTCGGGAAGTGCCCCAGGTATGTGAAGCAG CGGTCACTGCTGTTGGCTACTGGCATGAAAAACGTGCCGGAGATCCCAAAAGGCCGTGGG CTCTTCGGGGCTATCGCCGGGTTTATCGAGAACGGCTGGGAGGGCCTGATTAATGGGTGG TATGGCTTTAGGCATCAGAACGCGCAAGGAGAGGGAACCGCGGCCGACTATAAGAGCACA CAGTCTGCGATCGATCAAATAACCGGTAAGCTCAATCGGCTGATTGAAAAAACCAACCAG CAGTTTGAGCTAATCGACAATGAATTCAACGAGGTGGAAAAGCAGATTGGTAACGTCATT AATTGGACAAGAGACAGTATTACTGAGGTGTGGAGTTATAACGCTGAACTGCTGGTTGCC ATGGAGAATCAGCACACTATTGACCTGGCAGATTCTGAGATGGATAAGCTCTATGAGAGA GTGAAACGGCAGCTGAGAGAGAATGCTGAAGAGGATGGAACCGGGTGCTTCGAAATTTTT CATAAGTGTGATGACGATTGTATGGCCTCGATTAGAAATAATACATACGATCACTCCAAG TACCGAGAGGAGGCCATGCAGAACAGGATCCAAATTGACCCGGTTAAGCTGAGTAGTGGC TACAAGGATGTTATATTATGGTTTAGCTTCGGAGCCTCCTGCTTCATACTGCTGGCTATT GTGATGGGGTTAGTCTTTATCTGCGTGAAAAATGGGAACATGAGATGTACAATCTGTATA 678 ATGAACACGCAGATCCTAGTCTTTGCCCTTATTGCCATAATCCCTACCAACGCCGATAAG ATCTGCCTCGGTCACCACGCCGTTTCCAATGGCACAAAGGTGAATACTTTGACAGAACGG GGGGTTGAGGTGGTCAATGCTACCGAAACCGTAGAGCGAACAAATATCCCGAGAATATGT TCCAAAGGCAAGAAGACCGTGGACCTCGGACAGTGTGGATTACTCGGGACAATCACAGGT CCCCCACAGTGCGATCAGTTCTTGGAATTCTCTGCCGACCTCATTATCGAACGGAGAGAA GGATCGGATGTGTGTTATCCTGGCAAGTTCGTCAATGAGGAAGCTCTTAGACAGATCTTA CGCGAGAGTGGTGGCATCGACAAGGAAGCAATGGGTTTCACATATAGCGGAATTCGGACT AATGGAGCAACTTCAGCTTGTAGGAGAAGCGGCTCATCTTTTTATGCCGAAATGAAGTGG CTGTTATCTAACACCGATAACGCTGCCTTCCCACAGATGACGAAATCATACAAGAACACT AGGAAGAGCCCAGCTCTGATTGTGTGGGGTATTCATCATAGTGTCTCCACGGCGGAACAG ACTAAGCTGTATGGGTCCGGCAATAAACTTGTCACCGTAGGCAGCAGCAACTACCAGCAG AGCTTCGTGCCTAGCCCAGGAGCTAGGCCCCAGGTGAATGGACAGTCTGGGCGAATAGAC TTCCACTGGCTTATGCTCAATCCGAATGACACAGTGACATTCAGCTTCAATGGGGCTTTT ATTGCTCCAGACAGAGCCAGCTTCCTGAGAGGCAAATCAATGGGGATCCAAAGCGGAGTA CAGGTTGACGCCAACTGTGAAGGCGATTGCTACCACTCAGGGGGCACAATTATCTCTAAC CTGCCATTCCAGAATATTGATTCGAGAGCTGTGGGGAAGTGTCCTAGGTATGTAAAACAG CGGAGCCTGCTCCTCGCTACAGGGATGAAGAATGTCCCGGAAATCCCAAAAGGACGGGGC CTGTTTGGCGCAATTGCCGGCTTCATAGAGAATGGGTGGGAGGGACTGATCGATGGATGG TACGGGTTTCGCCACCAGAACGCCCAGGGAGAAGGGACAGCCGCTGATTACAAATCCACA CAAAGCGCAATCGACCAGATCACAGGTAAACTGAATAGGCTCATCGAGAAGACCAATCAG CAATTCGAACTTATCGACAATGAGTTTAATGAGGTGGAGAAACAAATCGGAAATGTGATC AATTGGACGCGAGATTCTATTACTGAGGTGTGGTCATACAATGCCGAACTCCTTGTGGCT ATGGAAAATCAGCACACCATAGACCTGGCCGACTCCGAGATGGATAAGCTATACGAGCGC GTCAAGCGCCAGCTGAGGGAAAATGCTGAGGAAGACGGAACGGGTTGCTTCGAAATTTTT CACAAGTGCGACGATGACTGCATGGCCTCTATTAGAAATAATACATACGACCACTCTAAG TATAGGGAAGAGGCCATGCAGAATCGCATACAGATCGATCCTGTGAAACTCTCCAGCGGG TATAAGGATGTCATTCTGTGGTTCAGTTTCGGCGCTAGCTGTTTTATACTTTTGGCTATT GTTATGGGTCTAGTGTTTATTTGCGTGAAAAACGGCAATATGCGGTGCACAATATGCATT 679 ATGAATACCCAGATCCTTGTCTTCGCATTAATAGCAATCATTCCAACCAATGCTGACAAG ATCTGTCTGGGTCACCATGCAGTTTCCAATGGCACAAAAGTTAATACACTGACAGAACGC GGGGTGGAAGTAGTCAACGCCACCGAAACCGTAGAGAGGACCAATATCCCCAGGATCTGC TCAAAGGGAAAGCGTACAGTGGACCTGGGACAGTGTGGGCTGCTCGGCACAATTACAGGA CCACCACAGTGTGACCAGTTCCTGGAGTTTAGCGCTGACTTAATAATCGAGAGAAGAGAG GGAAGCGACGTCTGTTATCCTGGCAAGTTTGTCAAGGAGGAGGCTCTTAGGCAGATCTTG AGAGAGTCGGGCGGCATAGATAAAGAGGCAATGGGATTCACCTATTCAGGGATTAGGACC AATGGTGCCACAAGTGCCTGCAGAAGATCAGGCTCTAGTTTTTACGCTGAGATGAAGTGG CTTCTGTCGAACACAGATAACGCCGCGTTCCCTCAGATGACTAAGTCATACAAAAATACA CGCAAAAGTCCTGCCTTAATCGTGTGGGGGATACATCATAGTGTATCCACCGCCGAGCAG ACTAAGCTCTACGGTAGCGGTAATAAGCTGGTCACTGTGGGCAGTTCCAACTACCAGCAG AGTTTTGTTCCCAGCCCCGGTGCTCGTCCCCAAGTGAACGGACTTAGCGGTAGGATTGAC TTTCATTGGCTGATGTTGAATCCTAATGACACGGTCACTTTTAGTTTCAACGGCGCTTTC ATCGCTCCCGATAGAGCTTCCTTCTTGCGCGGAAAGAGTATGGGGATACAGTCAGGCGTG CAGGTCGACGCGAATTGTGAAGGGGATTGCTACCATAGTGGAGGCACTATTATCTCAAAC CTCCCTTTCCAGAACATCGACAGTAGGGCCGTGGGAAAATGCCCTAGGTACGTTAAGCAG AGATCCCTATTGCTGGCCACGGGTATGAAGAATGTCCCCGAAATTCCAAAAGGAAGAGGA CTGTTCGGCGCCATCGCTGGCTTTATCGAGAACGGGTGGGAGGGGCTCATCGACGGGTGG TACGGGTTCAGACACCAGAATGCCCAAGGGGAGGGCACCGCCGCTGACTACAAATCTACG CAAAGTGCCATTGACCAGATTACCGGAAAGCTCAACCGGCTGATTGAGAAGACCAACCAG CAATTTGAGCTAATTGACAATGAATTTAACGAGGTCGAGAAGCAAATTGGGAACGTCATA AACTGGACTAGGGATTCAATTACCGAAGTCTGGAGCTATAACGCAGAACTATTGGTCGCT ATGGAGAACCAGCACACAATCGATCTCGCTGATTCTGAGATGGATAAGCTGTATGAGAGG GTGAAGAGACAGTTGAGGGAGAATGCTGAGGAGGATGGTACCGGCTGTTTTGAAATCTTT CATAAGTGTGACGATGACTGTATGGCTTCAATCCGGAACAATACGTACGATCACAGTAAA TATAGGGAAGAAGCTATGCAGAACAGAATTCAGATTGATCCTGTGAAACTAAGCAGTGGT TATAAAGATGTGATCCTCTGGTTCAGTTTCGGCGCCAGCTGTTTCATCCTGCTCGCCATC GTAATGGGACTGGTCTTCATATGCGTGAAGAATGGAAACATGCGTTGCACCATCTGTATT 680 ATGAATACACAGATTCTGGTGTTCGCTTTGATAGCGATCATTCCAACAAATGCAGACAAG ATCTGCCTCGGTCATCACGCGGTTTCAAATGGCACCAAAGTGAACACTCTCACCGAACGG GGGGTCGAGGTAGTTAACGCGACCGAGACTGTGGAGCGTACTAATATCCCCAGGATCTGT TCAAAGGGAAAGAGAACTGTGGACCTTGGGCAGTGTGGTCTGCTGGGCACCATCACTGGC CCCCCCCAGTGTGACCAGTTCCTGGAGTTCTCAGCCGACCTTATAATTGAGCGACGCGAA GGATCTGATGTATGCTACCCAGGCAAGTTTGTGAAAGAGGAGGCGTTACGCCAGATTCTG AGAGAGTCTGGTGGGATCGACAAAGAAGCGATGGGTTTCACATACAGCGGGATCCGGACC AACGGTGCCACCTCGGCATGTCGTCGTAGCGGCTCATCCTTCTACGCCGAGATGAAATGG CTGCTGTCAAACACCGACAACGCCGCTTTCCCGCAGATGACTAAGAGCTACAAAAACACC AGAAAGTCACCCGCCCTGATTGTGTGGGGAATTCATCACTCTGTGTCTACCGCCGAACAG ACCAAATTGTATGGTTCGGGGAATAAGCTGGTTACGGTAGGATCGTCAAATTACCAACAA AGCTTTGTGCCCTCTCCAGGAGCCAGACCTCAGGTAAACGGCCTCTCAGGAAGGATTGAC TTCCACTGGCTGATGCTGAATCCCAATGATACCGTAACATTCTCATTTAATGGCGCGTTC ATCGCACCGGATAGGGCATCCTTCTTAAGGGGGAAGAGTATGGGCATCCAGTCCGGGGTT CAAGTGGATGCCAATTGCGAAGGCGATTGTTACCACTCCGGAGGAACGATTATTAGCAAT CTGCCCTTCCAAAACATCGACTCTAGGGCCGTGGGCAAATGCCCTAGATATGTGAAGCAG AGGTCCCTGCTCCTAGCGACTGGCATGAAGAATGTGCCCGAGATACCAAAAGGGAGAGGA CTATTCGGTGCCATCGCCGGGTTCATTGAAAACGGATGGGAAGGCCTCATCGATGGGTGG TACGGATTTCGGCACCAGAATGCGCAAGGGGAAGGTACTGCTGCTGATTATAAGAGCACT CAGAGCGCTATTGATCAGATTACCGGTAAATTGAACCGTCTCATTGAAAAGACGAACCAG CAGTTCGAGCTGATCGATAATGAGTTTAATGAAGTGGAAAAGCAAATCGGGAACGTGATC AACTGGACAAGAGACTCAATCACTGAAGTCTGGTCCTACAATGCCGAGCTTTTGGTTGCC ATGGAGAACCAGCATACGATCGACCTTGCCGATAGCGAGATGGACAAACTATACGAGCGA GTCAAGAGGCAACTCAGAGAAAATGCAGAAGAGGATGGAACCGGCTGTTTCGAGATCTTT CATAAGTGCGACGACGATTGCATGGCTTCCATTAGAAATAACACCTACGACCACTCTAAG TATAGAGAGGAGGCTATGCAAAATCGCATCCAGATTGATCCGGTGAAACTCTCCTCGGGG TACAAAGATGTGATCCTGTGGTTCTCCTTTGGCGCAAGCTGTTTCATTTTATTAGCTATT GTGATGGGGCTCGTCTTTATCTGCGTGAAGAATGGCAACATGCGGTGTACCATCTGTATA 681 ATGAACACTCAGATACTCGTCTTTGCGCTCATCGCTATTATTCCTACCAACGCGGATAAA ATTTGCCTCGGGCACCACGCAGTGTCCAACGGAACTAAAGTGAACACGCTGACTGAACGT GGTGTGGAAGTGGTGAACGCAACAGAAACAGTGGAAAGGACTAATATTCCGCGTATATGC AGTAAGGGTAAGAAGACGGTCGACCTGGGGCAGTGCGGGCTTCTCGGTACCATCACGGGT CCTCCTCAGTGTGATCAGTTCCTTGAGTTTTCAGCCGACCTCATCATTGAACGTCGTGAG GGAAGTGATGTTTGTTATCCCGGGAAGTTCGTGAACGAAGAGGCATTGAGACAGATTCTG CGGGAGTCTGGGGGAATCGATAAGGAGGCCATGGGTTTCACATACTCCGGTATCAGGACT AACGGCGCAACCTCCGCCTGCCGGCGAAGCGGCAGCTCTTTCTACGCTGAAATGAAGTGG CTGTTGTCTAACACCGATAACGCCGCTTTCCCTCAGATGACCAAATCCTATAAGAATACG AGAAAGTCTCCTGCTCTCATCGTATGGGGGATCCACCATAGTGTGTCTACCGCCGAGCAG ACCAAACTGTACGGCTCAGGCAACAAATTGGTGACTGTAGGGAGCAGTAATTATCAGCAA AGCTTCGTTCCTTCCCCTGGAGCCAGACCTCAGGTGAATGGACAGTCAGGGCGGATCGAT TTCCATTGGCTGATGCTGAACCCAAACGATACAGTGACATTCTCATTCAATGGCGCGTTC ATAGCCCCAGATCGCGCCTCTTTCCTGCGCGGGAAATCAATGGGCATTCAATCTGGGGTA CAGGTGGACGCTAACTGTGAGGGGGACTGCTATCATTCCGGGGGCACAATTATTAGTAAC CTCCCTTTCCAGAACATTGATTCCAGAGCCGTGGGTAAGTGCCCGCGGTACGTGAAGCAG AGGTCACTGCTGCTAGCCACCGGAATGAAAAATGTGCCTGAAATCCCAAAAGGACGGGGC TTATTCGGCGCTATTGCTGGCTTCATCGAAAATGGGTGGGAGGGGTTGATCGACGGTTGG TACGGGTTCCGCCACCAGAACGCTCAGGGCGAAGGAACCGCCGCTGACTATAAGTCCACC CAGTCTGCCATCGACCAGATCACAGGAAAACTGAATAGGCTGATAGAAAAAACCAATCAG CAGTTCGAACTGATTGACAACGAGTTCAACGAGGTCGAGAAACAGATCGGAAATGTTATT AATTGGACCCGAGATAGCATCACTGAAGTCTGGTCCTATAACGCTGAGCTTCTAGTAGCG ATGGAAAATCAGCACACGATCGACCTGGCAGATAGCGAAATGGACAAACTCTACGAGAGA GTGAAGCGCCAGCTTCGAGAAAACGCCGAAGAAGATGGAACTGGGTGCTTTGAAATTTTC CACAAGTGTGATGACGATTGCATGGCCTCTATCCGCAATAATACCTACGATCACAGTAAA TATCGCGAAGAAGCGATGCAAAATCGTATCCAGATCGATCCTGTAAAGCTCAGCTCCGGA TACAAAGACGTGATTCTCTGGTTCAGTTTTGGCGCCAGCTGTTTTATCCTGCTCGCCATA GTCATGGGTTTGGTATTTATCTGCGTCAAGAACGGGAACATGCGTTGCACAATCTGCATA 682 ATGAATACTCAAATCCTGGTATTCGCCCTAATTGCAATCATTCCAACCAACGCTGACAAG ATCTGTTTAGGCCACCACGCCGTTTCGAACGGTACAAAGGTGAATACCCTGACAGAGAGG GGCGTGGAAGTGGTGAACGCGACAGAGACCGTGGAACGGACCAATATCCCCCGCATTTGC TCCAAGGGAAAAAAAACTGTAGACCTCGGACAGTGCGGCCTGCTCGGAACGATCACCGGA CCCCCTCAGTGCGACCAATTTCTGGAATTTAGTGCAGATCTCATTATTGAGAGGCGGGAA GGAAGTGACGTTTGCTATCCCGGCAAATTTGTGAATGAAGAGGCCCTTCGCCAGATCCTC AGAGAAAGCGGGGGCATAGACAAAGAGGCCATGGGCTTTACCTATTCTGGCATTCGAACC AACGGCGCTACCAGTGCTTGCAGACGGAGCGGCTCGTCCTTCTACGCAGAGATGAAGTGG CTTTTGTCCAATACCGACAACGCTGCTTTCCCTCAGATGACCAAGTCTTACAAGAACACC CGAAAGTCTCCAGCGCTGATTGTGTGGGGGATTCATCACTCAGTGAGTACAGCAGAGCAG ACTAAGCTGTATGGATCCGGCAATAAACTCGTGACTGTAGGTTCCTCAAATTATCAACAG AGCTTTGTCCCCTCTCCAGGAGCCAGGCCCCAGGTGAACGGACAATCTGGGCGTATAGAT TTTCACTGGCTGATGTTAAATCCAAACGACACCGTAACCTTCTCGTTTAATGGAGCCTTT ATCGCTCCTGACAGAGCGAGCTTTTTAAGAGGAAAAAGTATGGGAATACAGTCCGGAGTT CAGGTGGATGCCAACTGTGAGGGTGATTGCTACCACAGTGGCGGTACAATTATCAGTAAT CTACCCTTCCAAAATATCGATTCTCGGGCAGTGGGCAAGTGTCCCCGCTATGTCAAGCAG CGGAGCCTTCTCTTGGCAACAGGTATGAAAAACGTGCCTGAAATCCCTAAAGGAAGGGGC CTGTTCGGTGCCATTGCAGGATTTATCGAGAATGGGTGGGAAGGGCTTATTGACGGGTGG TATGGATTCCGGCACCAGAATGCCCAGGGGGAAGGCACCGCCGCTGACTACAAATCTACA CAGAGTGCCATTGATCAGATCACGGGCAAACTCAACAGACTTATCGAGAAGACAAATCAG CAATTTGAGCTGATAGACAATGAGTTCAATGAAGTGGAAAAACAGATCGGGAATGTGATT AACTGGACCAGAGATTCCATCACAGAGGTCTGGTCCTATAACGCCGAACTGCTCGTTGCC ATGGAAAACCAGCATACCATCGATCTTGCCGATTCCGAGATGGACAAGCTCTATGAACGC GTCAAGCGACAGCTCAGAGAAAATGCAGAGGAGGATGGGACAGGATGTTTTGAAATTTTC CACAAGTGCGATGACGACTGTATGGCATCCATTCGCAACAACACATACGATCACAGCAAG TATAGAGAGGAGGCCATGCAGAACAGAATACAGATCGATCCAGTTAAACTGAGTTCTGGC TATAAGGATGTGATTCTCTGGTTCTCTTTCGGAGCCAGCTGCTTTATCCTGCTGGCTATC GTCATGGGCCTGGTGTTCATCTGCGTCAAGAATGGAAACATGCGGTGCACGATTTGCATT 683 ATGAATACTCAGATCCTTGTGTTCGCCTTAATCGCCATCATCCCTACTAACGCCGACAAG ATCTGCCTGGGCCACCACGCTGTTTCCAATGGCACGAAGGTCAACACTCTCACCGAAAGA GGGGTTGAGGTGGTGAACGCCACCGAAACAGTAGAGAGAACGAACATCCCCCGTATTTGC TCCAAGGGGAAACGCACTGTGGATTTAGGACAGTGCGGCCTGCTGGGGACAATTACCGGA CCTCCTCAGTGCGACCAATTCCTGGAATTTTCAGCTGACCTCATCATAGAGCGGCGAGAG GGGTCCGATGTATGCTACCCTGGAAAGTTTGTGAATGAAGAGGCCCTTCGGCAGATCCTG CGCGAGAGCGGGGGGATTGATAAGGAAGCCATGGGTTTTACCTATTCCGGAATTAGAACG AACGGCGCTACATCAGCTTGCCGCCGTTCAGGTTCCAGCTTCTATGCCGAGATGAAGTGG CTACTTTCCAATACCGACAATGCGGCATTCCCTCAGATGACTAAGTCTTACAAGAATACT CGGAAGTCACCAGCCCTTATCGTCTGGGGCATTCACCACAGCGTGTCAACCGCGGAGCAA ACCAAACTATATGGGTCGGGGTCTAAACTCGTAACCGTGGGTTCGAGCAATTACCAGCAG AGCTTCGTTCCCAGTCCTGGCGCTCGACCTCAGGTGAATGGGCTGAGTGGGAGGATAGAC TTTCATTGGTTAATGTTAAATCCTAACGATACTGTCACCTTCTCCTTCAATGGTGCTTTC ATTGCACCAGACCGTGCTAGCTTCCTCCGCGGGAAATCGATGGGCATACAGTCCGGAGTG CAAGTCGACGCTAACTGTGAAGGCGATTGTTACCATTCAGGCGGCACCATAATCAGCAAT CTGCCTTTTCAGAACATTGATAGTCGTGCTGTGGGAAAGTGTCCTAGATACGTGAAGCAG AGGAGTCTTCTTTTGGCCACTGGCATGAAAAACGTACCAGAGATCCCCAAAGGACGGGGC CTGTTTGGCGCTATCGCGGGCTTTATAGAAAATGGCTGGGAGGGATTAATCGACGGCTGG TACGGTTTTAGGCACCAGAATGCCCAAGGCGAAGGTACAGCAGCCGATTACAAAAGTACA CAGTCCGCCATCGATCAGATTACCGGGAAACTCAATCGTCTCATTGAGAAGACAAACCAA CAGTTTGAGCTTATAGACAACGAATTTAATGAAGTGGAGAAACAGATTGGAAACGTAATC AACTGGACACGGGACTCCATAACTGAGGTCTGGAGCTACAATGCTGAACTCTTGGTGGCC ATGGAGAACCAGCATACCATTGACTTGGCAGACTCTGAGATGGATAAGCTGTACGAAAGG GTGAAACGGCAGCTTCGTGAAAATGCCGAGGAGGATGGCACCGGATGTTTTGAGATATTC CACAAGTGTGATGACGACTGCATGGCGAGCATTCGTAACAATACTTACGATCACTCAAAG TACCGGGAGGAAGCCATGCAGAATAGAATCCAGATCGATCCTGTGAAGCTGTCCTCGGGC TACAAGGACGTCATCCTGTGGTTCTCCTTTGGCGCTAGCTGTTTCATTCTGTTGGCGATC GTTATGGGTCTCGTCTTTATTTGCGTTAAGAACGGCAACATGCGTTGCACAATTTGCATT 684 ATGAATACTCAAATTCTCGTCTTTGCCCTGATTGCTATCATTCCCACCAATGCAGACAAG ATTTGCCTCGGTCACCACGCCGTATCAAACGGCACAAAAGTGAACACACTGACCGAAAGA GGTGTCGAGGTCGTTAATGCCACTGAGACCGTTGAGCGGACTAACATCCCTAGAATCTGC AGCAAGGGGAAGAAAACTGTGGATCTTGGGCAGTGCGGACTGCTGGGAACAATAACCGGG CCTCCCCAATGCGACCAATTCCTGGAGTTTTCCGCTGATCTCATTATTGAGCGCAGAGAA GGGAGCGATGTATGCTACCCCGGAAAGTTTGTCAACGAGGAAGCTTTGCGCCAGATTCTG AGGGAATCTGGCGGCATCGACAAAGAGGCTATGGGATTCACATACAGTGGTATAAGGACT AATGGAGCAACCAGCGCTTGTCGGCGGTCGGGGAGCTCCTTTTATGCTGAAATGAAATGG CTGCTTTCTAACACTGATAACGCTGCCTTCCCCCAGATGACTAAATCGTACAAGAACACA CGAAAATCGCCGGCACTGATCGTGTGGGGAATACACCATTCAGTGTCCACTGCCGAACAG ACCAAACTGTATGGCAGCGGCAACAAGCTCGTGACCGTTGGTTCCTCGAACTATCAGCAA AGCTTCGTGCCTTCGCCAGGTGCTCGCCCTCAGGTCAATGGACAGTCCGGAAGGATTGAC TTTCACTGGCTTATGTTGAACCCGAACGATACTGTTACATTTAGTTTTAACGGCGCCTTT ATTGCACCCGACAGGGCCTCATTTTTGCGAGGCAAGTCGATGGGCATACAATCTGGCGTG CAGGTAGATGCAAACTGTGAAGGCGATTGCTATCACTCCGGAGGCACAATTATTAGTAAT CTACCCTTCCAGAATATCGACTCTCGGGCGGTCGGCAAATGTCCCCGATACGTAAAGCAA CGCTCCCTGTTGCTGGCCACTGGTATGAAGAACGTCCCTGAAATCCCCAAAGGCCGGGGA TTGTTCGGCGCCATAGCAGGATTCATCGAGAACGGCTGGGAAGGTCTCATAGATGGTTGG TATGGTTTCCGTCACCAGAACGCCCAGGGGGAAGGCACCGCAGCGGATTACAAGTCGACG CAGTCTGCAATCGACCAGATCACCGGTAAACTGAACCGCCTGATTGAGAAAACAAACCAA CAATTCGAATTAATTGACAATGAGTTTAATGAGGTAGAGAAACAGATTGGCAACGTGATT AACTGGACAAGGGATTCAATTACCGAAGTTTGGAGCTACAACGCCGAGTTGCTGGTCGCT ATGGAAAACCAGCACACAATCGACCTGGCCGACTCCGAGATGGACAAGTTATATGAACGG GTGAAACGGCAGCTGCGGGAGAATGCCGAGGAGGATGGTACAGGGTGTTTTGAAATCTTT CACAAATGTGATGATGATTGCATGGCGTCAATACGCAACAACACATATGACCACTCAAAA TATCGAGAAGAAGCCATGCAGAACAGAATACAGATTGACCCCGTGAAGCTTTCAAGTGGC TATAAAGATGTCATTCTGTGGTTCTCCTTCGGGGCATCCTGCTTTATCCTGCTCGCCATC GTTATGGGGCTTGTGTTCATTTGTGTCAAGAATGGAAACATGAGGTGCACCATCTGCATC 685 ATGAATACCCAGATCCTGGTTTTTGCCCTGATCGCTATCATACCAACAAACGCTGACAAG ATCTGTCTTGGCCACCACGCTGTCTCTAATGGGACCAAAGTCAATACCCTGACCGAAAGG GGAGTGGAGGTAGTCAACGCTACTGAGACAGTCGAAAGAACTAATATTCCTAGAATTTGC AGTAAGGGCAAGAAAACCGTGGATCTGGGGCAGTGTGGCCTGCTGGGCACCATAACCGGG CCTCCTCAGTGCGATCAGTTCCTGGAGTTTTCCGCCGATCTGATCATTGAACGCAGGGAA GGCAGCGACGTATGCTACCCAGGGAAGTTTGTTAATGAGGAAGCACTCCGCCAGATTCTC CGAGAGTCTGGGGGTATTGATAAGGAGGCAATGGGTTTTACATACAGCGGCATTAGGACT AATGGGGCTACTTCAGCTTGCCGAAGGAGCGGATCTTCCTTTTACGCTGAGATGAAATGG CTCCTGAGCAATACCGACAATGCCGCCTTTCCTCAGATGACGAAATCTTATAAGAACACA AGAAAGTCCCCAGCACTGATCGTGTGGGGGATTCACCACTCAGTCTCCACAGCCGAGCAG ACCAAGCTGTACGGCTCAGGCAATAAACTCGTGACGGTTGGCAGCTCCAATTACCAGCAG TCCTTTGTCCCTAGTCCTGGAGCCCGGCCTCAGGTGAATGGGCAGTCCGGTCGAATAGAC TTTCACTGGCTCATGTTAAACCCCAATGACACAGTGACCTTCAGCTTCAATGGGGCTTTC ATCGCCCCCGACCGTGCCAGCTTTCTGCGGGGGAAAAGCATGGGGATACAGTCTGGGGTT CAGGTGGATGCCAATTGTGAAGGGGACTGTTACCACTCTGGGGGCACCATCATCAGTAAT TTACCATTCCAGAATATTGACTCGAGAGCCGTAGGAAAGTGCCCCAGGTACGTGAAGCAG AGATCTCTGCTGCTTGCGACGGGTATGAAAAATGTCCCAGAGATCCCGAAAGGCCGGGGA CTTTTTGGAGCAATCGCCGGCTTCATCGAGAATGGCTGGGAAGGGCTGATCGACGGCTGG TACGGCTTTCGCCACCAGAACGCCCAGGGCGAGGGTACAGCGGCAGACTATAAGTCCACT CAGAGTGCCATCGATCAGATCACAGGTAAGCTCAATCGTCTCATTGAGAAGACCAATCAG CAGTTCGAGCTCATCGACAACGAATTCAACGAGGTTGAGAAACAGATCGGCAACGTGATC AACTGGACAAGGGACAGTATCACCGAGGTGTGGAGCTACAACGCTGAGCTGCTGGTGGCT ATGGAAAACCAGCACACCATCGATCTGGCAGATTCCGAAATGGATAAGCTTTATGAGCGG GTGAAGCGTCAACTGAGAGAGAACGCCGAGGAGGATGGAACTGGCTGCTTCGAAATCTTT CATAAATGTGATGACGACTGCATGGCCTCAATCCGGAATAACACTTATGACCACAGCAAA TACAGAGAAGAGGCGATGCAGAATCGAATCCAGATAGACCCCGTCAAGCTTTCATCGGGT TATAAGGACGTTATCCTATGGTTTTCTTTTGGCGCCAGCTGCTTTATCCTCCTCGCGATT GTCATGGGACTTGTGTTCATTTGCGTGAAAAACGGCAATATGCGCTGTACAATTTGTATC 686 ATGAACACACAGATTCTGGTTTTCGCCTTGATTGCCATTATTCCTACTAATGCAGACAAG ATCTGTTTGGGCCATCACGCCGTAAGTAACGGTACGAAGGTCAACACCTTGACAGAGCGC GGGGTTGAGGTTGTCAATGCAACAGAAACCGTCGAACGGACAAACATCCCAAGGATCTGC TCAAAAGGCAAGAAAACCGTCGACCTGGGGCAATGTGGCCTTCTCGGAACTATAACCGGA CCCCCACAATGCGATCAATTTCTGGAGTTCAGCGCTGACCTAATAATAGAGAGACGGGAG GGGTCAGATGTGTGTTATCCGGGGAAATTCGTGAACGAAGAAGCCCTTAGGCAGATCTTA CGGGAAAGCGGTGGCATCGACAAAGAGGCCATGGGATTTACCTACAGCGGGATCCGGACG AACGGTGCCACTAGTGCATGTCGGAGGTCGGGAAGCTCTTTTTACGCCGAGATGAAGTGG CTTCTGAGCAATACAGATAATGCTGCTTTCCCGCAGATGACAAAGTCTTACAAGAATACA AGAAAATCCCCAGCTCTCATAGTCTGGGGTATCCATCATTCTGTATCCACGGCCGAGCAA ACCAAACTTTACGGCTCTGGGAATAAACTGGTGACAGTGGGATCATCTAATTATCAGCAG TCTTTCGTGCCATCACCAGGCGCACGACCGCAAGTTAACGGACAGTCTGGTAGAATCGAC TTTCATTGGCTAATGCTGAACCCGAATGATACTGTGACCTTCAGTTTCAATGGGGCTTTC ATAGCACCAGACAGGGCATCATTTCTCAGAGGAAAATCAATGGGCATTCAGTCTGGTGTG CAGGTGGATGCAAATTGCGAGGGAGACTGCTATCACAGTGGCGGCACTATCATCTCGAAT CTCCCGTTCCAGAATATCGATAGCCGCGCCGTGGGGAAGTGCCCTCGGTACGTTAAACAA CGATCTCTGCTGTTAGCCACCGGCATGAAGAATGTACCCGAGATCCCTAAGGGTCGAGGC CTCTTTGGCGCCATTGCTGGCTTTATCGAGAATGGCTGGGAAGGACTCATAGACGGCTGG TATGGGTTCCGGCATCAGAACGCTCAGGGAGAAGGGACCGCTGCGGACTATAAGTCAACA CAGTCCGCCATTGACCAAATCACAGGCAAGCTGAACCGGCTGATTGAAAAAACTAATCAA CAATTCGAGCTGATAGATAACGAGTTCAACGAAGTCGAAAAGCAGATTGGCAATGTCATT AATTGGACACGCGATAGCATCACTGAAGTGTGGAGCTACAACGCAGAGCTGCTGGTTGCC ATGGAGAACCAGCACACCATCGATCTGGCTGACTCTGAGATGGACAAGCTGTACGAACGG GTGAAGCGTCAGCTCCGTGAGAACGCTGAAGAAGATGGGACAGGTTGCTTCGAAATCTTT CATAAATGCGACGACGATTGTATGGCCTCAATAAGGAACAATACATATGACCACTCTAAG TATAGAGAGGAGGCCATGCAGAATCGTATCCAGATCGATCCAGTGAAGCTGTCTTCAGGG TACAAAGATGTGATCCTCTGGTTTTCATTCGGTGCCAGCTGTTTTATCTTACTGGCCATC GTCATGGGCCTCGTCTTCATTTGTGTGAAAAACGGTAACATGAGATGCACCATTTGTATT 687 ATGAATACGCAGATTTTGGTGTTCGCCCTGATCGCCATAATCCCCACTAACGCCGACAAA ATCTGTCTGGGGCACCACGCGGTGTCTAATGGGACTAAGGTAAACACACTGACAGAGAGA GGCGTTGAGGTTGTTAACGCCACGGAGACAGTAGAACGTACAAACATCCCCCGCATCTGC TCCAAGGGCAAAAAGACTGTGGATCTGGGGCAGTGCGGTTTGCTCGGAACCATTACAGGC CCCCCTCAGTGTGACCAATTTCTTGAATTCTCCGCCGACCTCATCATCGAGCGCCGGGAA GGAAGTGATGTTTGCTATCCCGGGAAATTTGTGAATGAGGAAGCCCTGAGGCAAATTCTC CGGGAGTCAGGGGGTATTGACAAAGAGGCTATGGGGTTTACATACTCCGGTATCCGTACC AATGGAGCAACCTCGGCTTGCCGTAGGTCCGGCAGCTCCTTTTACGCTGAGATGAAATGG CTGCTCTCGAACACCGACAATGCCGCATTTCCCCAGATGACTAAGTCTTACAAGAATACC CGGAAGTCTCCGGCCCTGATTGTGTGGGGAATCCACCATTCCGTGTCCACCGCCGAACAG ACTAAGCTTTACGGCTCGGGCAACAAACTGGTCACCGTTGGCTCTTCTAACTATCAGCAG AGCTTTGTGCCTTCACCAGGGGCTCGACCTCAGGTGAACGGGCAGTCCGGCCGGATCGAT TTCCACTGGCTAATGCTGAACCCAAATGATACTGTTACGTTTTCCTTCAATGGTGCTTTT ATAGCACCTGATCGCGCTTCCTTTCTGAGGGGGAAAAGCATGGGCATACAATCTGGGGTT CAGGTTGATGCCAACTGTGAGGGGGATTGCTATCACTCTGGTGGGACCATAATTTCCAAC CTCCCCTTTCAGAACATCGACTCACGAGCCGTCGGTAAGTGTCCAAGATACGTGAAGCAA CGCTCATTACTCCTGGCTACCGGAATGAAAAATGTTCCAGAGATCCCGAAGGGGAGGGGT CTGTTCGGTGCCATTGCGGGATTTATTGAAAACGGATGGGAGGGACTAATCGACGGATGG TATGGGTTTAGGCATCAGAACGCACAGGGCGAGGGAACCGCCGCGGACTATAAAAGCACT CAGTCCGCCATTGATCAGATTACAGGGAAACTCAATAGACTCATTGAGAAGACGAATCAG CAGTTCGAGCTGATCGACAACGAGTTCAATGAGGTCGAAAAACAGATCGGGAATGTGATA AATTGGACTAGGGATTCAATAACAGAGGTCTGGAGCTACAACGCAGAGTTACTCGTTGCG ATGGAGAACCAACATACTATTGATCTTGCAGACTCCGAGATGGATAAGCTATACGAGCGG GTCAAGCGACAGTTAAGGGAGAATGCAGAAGAAGATGGAACTGGGTGCTTCGAAATATTT CATAAGTGCGACGACGACTGTATGGCCTCAATCCGCAACAACACATACGACCACTCAAAG TACAGGGAGGAAGCCATGCAGAACCGGATCCAAATTGACCCGGTGAAACTGAGCTCTGGC TACAAGGACGTGATCCTATGGTTTTCTTTTGGGGCCAGTTGCTTCATCCTACTCGCTATA GTCATGGGTCTGGTGTTCATTTGTGTCAAGAACGGGAACATGCGTTGTACTATCTGCATT 688 ATGAATACCCAAATCTTGGTGTTCGCGTTGATCGCAATCATCCCCACTAACGCCGACAAA ATCTGTTTAGGGCATCACGCTGTTTCCAACGGTACGAAAGTGAATACACTGACTGAACGC GGGGTCGAGGTCGTTAACGCTACAGAGACGGTGGAGAGAACTAATATCCCTAGGATCTGC TCCAAGGGCAAGCGCACTGTGGACCTGGGGCAATGCGGACTGCTAGGGACAATTACTGGC CCGCCCCAGTGCGACCAATTTTTGGAGTTTAGCGCAGACCTGATCATAGAGCGACGCGAG GGTTCAGACGTTTGTTACCCTGGAAAGTTTGTAAATGAGGAAGCCCTTCGCCAGATCCTG CGGGAGAGCGGCGGTATCGATAAAGAGGCTATGGGGTTTACGTACTCTGGAATCAGAACC AATGGGGCCACCTCTGCTTGTAGAAGATCTGGATCCTCCTTTTATGCAGAAATGAAGTGG TTGTTATCAAATACTGATAACGCGGCATTTCCACAGATGACTAAGAGCTACAAGAACACG CGGAAGTCACCCGCTTTAATAGTCTGGGGCATCCACCACTCAGTTAGTACAGCTGAGCAG ACTAAGCTGTATGGCAGTGGTAACAAGCTGGTCACCGTGGGTAGCTCTAATTATCAGCAA TCTTTCGTACCATCACCCGGAGCTAGACCTCAGGTGAACGGTCTGTCAGGCCGGATCGAC TTCCACTGGTTGATGCTCAATCCCAATGACACTGTTACATTCAGCTTTAATGGCGCCTTC ATCGCTCCTGACCGAGCCAGCTTTCTGCGCGGCAAGTCTATGGGGATCCAATCTGGCGTG CAGGTTGATGCGAACTGCGAAGGGGACTGCTACCACAGTGGAGGCACCATCATTTCTAAC CTGCCATTCCAGAATATCGACAGTCGCGCCGTGGGGAAGTGTCCTCGATACGTGAAGCAG AGGAGCCTCCTCCTAGCGACTGGAATGAAGAACGTCCCAGAAATCCCTAAGGGCCGGGGG CTCTTTGGAGCGATTGCCGGATTTATCGAAAACGGCTGGGAAGGGCTTATTAATGGCTGG TACGGCTTCAGGCATCAGAATGCTCAAGGCGAGGGAACTGCCGCCGACTACAAGTCCACT CAATCCGCCATTGATCAGATAACCGGGAAACTTAACCGCCTGATCGAGAAGACAAACCAG CAGTTTGAGCTGATAGATAATGAGTTCAATGAAGTCGAGAAACAGATAGGAAACGTCATT AATTGGACCCGCGACTCAATTACAGAAGTCTGGAGCTATAACGCAGAGCTGTTGGTAGCG ATGGAAAACCAACACACAATTGACCTGGCCGATTCCGAAATGGATAAGCTGTACGAGCGC GTGAAAAGACAGTTAAGGGAAAATGCCGAGGAAGATGGTACCGGCTGTTTCGAGATCTTC CACAAGTGCGATGATGATTGCATGGCCTCCATCCGAAATAATACTTACGATCACTCCAAG TACAGAGAGGAGGCAATGCAAAACAGAATTCAGATCGACCCCGTTAAGTTATCAAGCGGA TACAAGGACGTCATCCTGTGGTTCTCATTTGGCGCATCGTGTTTTATTCTGCTTGCTATT GTGATGGGTCTCGTTTTCATTTGTGTCAAGAACGGGAATATGAGGTGTACGATCTGCATC 689 ATGAACACCCAGATTTTAGTCTTTGCACTGATTGCAATTATTCCCACTAATGCTGACAAG ATCTGTCTGGGCCACCACGCTGTGTCAAACGGAACTAAGGTGAACACGCTGACTGAGCGA GGTGTCGAAGTGGTGAATGCGACGGAAACCGTGGAGAGAACAAATATCCCCAGAATCTGC AGTAAAGGAAAAAAAACTGTGGATCTGGGCCAATGCGGGCTGCTGGGTACTATCACCGGG CCACCACAATGCGACCAGTTTCTTGAGTTCTCCGCAGATCTCATCATCGAACGCCGGGAA GGCTCCGATGTTTGTTACCCAGGGAAGTTCGTAAATGAAGAAGCCTTAAGGCAAATCCTT AGAGAGAGCGGAGGAATTGAGAAAGAGGCAATGGGCTTTACCTACTCAGGAATTAGAGCC AACGGCGCTACTTCCGCTTGTCGACGAAGTGGCTCCAGTTTCTATGCCGAAATGAAGTGG CTGTTGTCTAACACGGATAACGCAGCCTTTCCTCAGATGACTAAGTCGTACAAAAACACC CGGAAATCTCCAGCTCTGATTGTGTGGGGAATCCACCATAGTGTGTCCACCGCCGAGCAA ACCAAACTTTATGGGAGCGGAAACAAGTTGGTTACTGTTGGATCCTCGAACTATCAGCAG AGCTTCGTGCCTAGCCCAGGCGCTCGTCCACAGGTGAACGGACTCTCCGGTAGAATCGAT TTTCATTGGCTTATGCTCAATCCTAATGACACTGTGACCTTTAGCTTCAACGGCGCGTTT ATCGCCCCTGATCGAGCCTCTTTCCTGCGCGGAAAGTCAATGGGTATCCAGTCGGGCGTT CAGGTGGATGCAAATTGCGAGGGGGACTGCTATCACTCTGGTGGCACCATTATCTCAAAC CTGCCATTTCAGAACATCGACTCCCGTGCGGTCGGTAAATGCCCGAGATACGTTAAGCAG CGAAGCCTGCTACTGGCAACAGGCATGAAGAACGTGCCTGAGATACCTAAGGGACGTGGT CTGTTTGGAGCAATTGCCGGGTTCATTGAGAATGGCTGGGAGGGGCTCATCGATGGGTGG TATGGCTTTAGACATCAAAATGCTCAGGGAGAAGGTACTGCAGCCGATTACAAGAGTACC CAGAGCGCCATCGATCAGATCACTGGCAAGTTAAACCGCCTTATCGAAAAGACCAACCAG CAGTTTGAGCTTATCGACAATGAATTTAACGAAGTGGAGAAGCAAATCGGCAACGTCATC AACTGGACTCGCGATTCTATCACCGAGGTCTGGTCATATAACGCAGAGTTACTCGTTGCG ATGGAAAACCAGCACACTATTGACTTGGCCGACTCTGAGATGGACAAACTGTACGAAAGA GTTAAAAGACAGCTGCGGGAAAACGCTGAGGAAGATGGGACTGGCTGTTTCGAGATCTTT CACAAATGCGATGACGACTGCATGGCTTCGATTCGGAATAATACATACGATCACTCTAAG TACAGAGAAGAGGCTATGCAGAACAGAATCCAAATCGATCCCGTTAAGCTGTCATCAGGC TACAAGGACGTGATCCTGTGGTTCTCTTTCGGGGCGAGTTGCTTTATCCTTCTTGCCATC GTGATGGGCCTTGTGTTTATTTGTGTTAAAAACGGTAACATGCGCTGTACAATCTGTATA 690 ATGAACACACAAATTCTGGTCTTCGCACTGATTGCAATCATCCCAACTAACGCTGACAAA ATTTGTCTGGGGCACCATGCGGTCAGTAATGGCACCAAGGTCAACACTCTCACTGAACGC GGAGTGGAAGTGGTGAACGCAACCGAGACAGTGGAGCGGACCAACATCCCCAGAATATGC TCAAAGGGTAAAAAGACTGTGGATTTGGGACAGTGCGGTCTTCTTGGGACAATCACCGGC CCTCCCCAGTGTGACCAGTTCCTGGAATTCTCTGCCGACCTGATTATAGAGCGGCGTGAG GGCTCCGATGTGTGTTACCCCGGCAAGTTCGTGAACGAGGAGGCACTGCGACAGATCTTG AGAGAAAGCGGGGGGATTGACAAAGAGGCTATGGGCTTCACTTATTCGGGCATCAGGACT AATGGCGCAACCTCCGCTTGTAGGAGATCAGGATCCTCTTTCTACGCCGAAATGAAGTGG CTGCTGTCGAATACAGACAATGCCGCTTTCCCCCAAATGACTAAGAGTTATAAAAACACG CGTAAATCCCCAGCGCTGATTGTCTGGGGAATCCACCACTCGGTGAGCACTGCAGAGCAG ACTAAACTGTACGGGAGCGGCAATAAACTTGTTACAGTGGGATCCTCGAATTACCAACAG AGCTTCGTCCCATCACCAGGTGCTCGACCACAGGTGAACGGCCAGTCTGGGCGAATAGAT TTTCATTGGCTCATGCTTAATCCCAATGACACTGTGACTTTTTCTTTCAATGGGGCCTTC ATCGCGCCTGATCGGGCCAGTTTCCTGAGAGGCAAGAGTATGGGAATCCAGTCCGGCGTG CAGGTGGACGCTAATTGTGAGGGGGATTGCTATCACTCAGGTGGCACTATAATTTCAAAT CTTCCTTTCCAGAACATCGATTCTCGAGCCGTCGGAAAGTGCCCTAGGTACGTGAAACAA AGGTCACTCCTTTTGGCAACCGGGATGAAGAACGTGCCAGAGATTCCCAAGGGTCGGGGG CTCTTTGGCGCTATTGCTGGATTTATCGAGAATGGGTGGGAGGGTCTGATAGACGGTTGG TATGGCTTCAGACACCAGAACGCCCAGGGGGAGGGCACCGCCGCCGACTATAAGAGTACC CAGAGCGCAATTGACCAGATTACCGGAAAATTGAACCGACTGATTGAGAAGACAAATCAG CAGTTTGAGTTGATCGACAACGAATTCAATGAGGTTGAAAAACAGATCGGGAACGTTATA AACTGGACACGAGATAGCATAACAGAGGTCTGGAGTTACAATGCTGAACTGCTGGTTGCT ATGGAAAACCAGCATACTATTGACCTTGCGGACAGCGAGATGGACAAACTATACGAAAGA GTGAAGCGCCAGCTGCGTGAGAACGCCGAAGAAGACGGGACTGGATGCTTCGAGATATTC CACAAGTGTGATGACGATTGTATGGCAAGCATACGGAACAACACATACGATCATAGCAAA TATAGGGAGGAGGCGATGCAGAACAGAATACAGATAGACCCTGTGAAGTTATCTTCCGGT TACAAAGACGTTATCCTCTGGTTTAGCTTCGGAGCCAGCTGCTTTATATTATTAGCCATC GTCATGGGCCTCGTTTTCATCTGCGTGAAGAATGGAAATATGCGCTGCACCATCTGCATC 691 ATGAATACGCAGATCTTGGTATTCGCACTTATAGCCATCATCCCCACCAACGCCGATAAG ATTTGCTTAGGCCACCATGCTGTTTCTAACGGCACAAAAGTGAACACACTTACCGAGAGA GGGGTCGAAGTTGTGAACGCCACGGAGACAGTCGAAAGGACAAACATTCCTCGAATCTGC AGTAAGGGCAAGAAAACAGTGGATCTCGGCCAGTGTGGGCTGCTGGGAACCATCACGGGT CCTCCGCAGTGTGACCAGTTCCTGGAGTTCTCTGCCGATCTCATCATCGAAAGGCGGGAG GGATCCGACGTGTGCTACCCAGGCAAATTCGTGAACGAAGAAGCGCTTCGGCAAATTCTG CGAGAGTCAGGGGGGATAGATAAAGAGGCAATGGGGTTTACTTATTCTGGCATTAGAACC AATGGGGCCACGAGTGCATGTAGACGGTCCGGAAGTAGCTTTTACGCAGAAATGAAGTGG CTGTTGTCTAACACTGACAACGCTGCATTTCCACAGATGACCAAGTCTTATAAAAACACG AGAAAATCCCCAGCCCTCATTGTGTGGGGGATCCACCATTCTGTGAGCACCGCCGAGCAA ACGAAGCTGTATGGCAGTGGTAACAAGCTAGTCACAGTAGGATCCAGTAATTACCAGCAA AGCTTCGTGCCCAGTCCCGGAGCTCGGCCTCAGGTCAACGGGCAATCTGGGAGAATCGAC TTCCACTGGCTGATGCTGAACCCAAACGACACAGTGACATTTTCTTTTAATGGCGCTTTC ATTGCCCCCGACAGGGCTAGTTTTCTGAGAGGCAAGTCCATGGGGATCCAAAGCGGAGTG CAGGTGGACGCTAATTGCGAGGGCGATTGTTACCACAGTGGGGGGACCATTATCAGTAAT CTGCCTTTCCAGAACATCGATAGTAGAGCCGTGGGCAAATGTCCACGTTACGTCAAGCAG CGGAGCCTGCTCTTAGCCACGGGCATGAAGAACGTGCCTGAGATCCCAAAGGGCAGAGGG CTGTTTGGCGCTATCGCGGGATTCATTGAAAATGGGTGGGAGGGACTAATCGACGGATGG TACGGTTTTCGACACCAGAACGCACAGGGGGAAGGGACAGCTGCCGATTATAAGTCTACT CAATCTGCTATCGACCAGATAACTGGGAAACTTAATCGGCTGATTGAGAAAACAAACCAG CAGTTTGAGCTGATAGACAACGAATTCAACGAAGTGGAGAAACAGATCGGTAACGTGATA AACTGGACTAGGGACTCTATCACCGAGGTGTGGTCCTACAACGCGGAACTCCTTGTCGCT ATGGAGAATCAGCACACTATAGACCTGGCAGACTCTGAAATGGATAAACTGTACGAACGG GTTAAGCGGCAATTGCGGGAGAACGCTGAGGAGGATGGCACAGGATGTTTTGAAATTTTT CATAAATGTGACGACGATTGCATGGCTTCCATTCGCAACAATACTTATGATCATTCGAAG TACCGGGAAGAGGCCATGCAAAACCGTATCCAGATCGATCCCGTCAAACTGTCGTCGGGG TACAAGGACGTTATACTTTGGTTCAGCTTTGGAGCCTCTTGTTTCATCTTGCTCGCTATA GTGATGGGCTTGGTGTTTATATGCGTAAAAAATGGCAACATGCGGTGCACAATTTGCATT 692 ATGAACACTCAGATACTCGTCTTTGCTCTCATTGCAATTATTCCTACCAATGCTGATAAG ATTTGCTTGGGGCACCACGCAGTTTCCAATGGGACAAAGGTGAACACCCTAACTGAGCGG GGCGTTGAAGTGGTGAACGCAACCGAGACAGTGGAAAGAACAAATATCCCCCGCATTTGC AGTAAAGGCAAAAAAACCGTCGACTTGGGACAGTGTGGCCTGCTTGGGACTATCACCGGA CCCCCACAGTGTGACCAATTTTTGGAGTTTTCAGCTGATCTGATTATCGAAAGACGCGAG GGAAGCGATGTTTGCTATCCAGGAAAATTTGTGAATGAAGAAGCACTCCGACAGATCCTG CGGGAGTCCGGCGGAATAGATAAGGAAGCAATGGGGTTCACTTACTCGGGCATCCGGACT AACGGAGCCACTTCCGCCTGCAGAAGGTCAGGCTCGTCGTTCTATGCCGAGATGAAGTGG CTGCTTTCAAACACTGATAATGCCGCATTCCCACAGATGACAAAGTCATACAAAAACACC AGGAAATCACCCGCATTGATAGTGTGGGGCATCCATCATTCTGTGTCCACTGCCGAGCAG ACTAAACTGTACGGGAGCGGGAATAAGCTTGTTACCGTCGGGTCAAGCAACTATCAGCAA AGTTTTGTACCAAGCCCGGGCGCACGGCCCCAGGTTAATGGTCAGTCCGGTCGCATTGAT TTCCATTGGCTAATGCTAAATCCAAATGACACTGTAACGTTCTCATTCAACGGAGCGTTC ATCGCTCCAGACCGTGCCTCTTTTCTGCGCGGGAAAAGCATGGGGATACAGTCCGGGGTG CAGGTAGATGCTAACTGTGAGGGAGACTGTTATCACTCTGGCGGCACGATCATCTCCAAC CTTCCCTTTCAGAACATTGACAGCAGAGCCGTCGGGAAATGCCCCCGATATGTTAAGCAG AGGTCACTTCTTCTCGCTACGGGTATGAAGAATGTCCCAGAAATTCCTAAAGGCCGGGGA TTGTTTGGAGCAATCGCCGGCTTCATCGAAAACGGTTGGGAAGGCTTGATTGATGGCTGG TACGGCTTCCGCCACCAAAATGCTCAGGGAGAAGGAACTGCAGCTGACTATAAATCAACA CAGAGCGCCATTGACCAGATCACAGGGAAGCTGAACAGACTTATCGAGAAAACCAATCAG CAGTTTGAGCTCATAGACAACGAATTTAACGAAGTGGAGAAACAGATTGGCAACGTTATC AATTGGACCCGGGACTCAATCACTGAAGTCTGGTCCTACAATGCAGAGCTGCTCGTCGCT ATGGAAAACCAGCACACTATCGATTTGGCTGACAGCGAAATGGATAAACTATATGAAAGG GTCAAGCGTCAGCTCCGAGAAAATGCAGAAGAGGATGGAACAGGCTGTTTCGAAATCTTC CATAAGTGTGATGACGATTGCATGGCCAGTATCAGAAACAACACTTACGATCACTCCAAA TACAGGGAGGAGGCCATGCAGAACCGGATCCAGATTGACCCTGTAAAACTGTCGAGCGGC TATAAAGATGTTATCCTGTGGTTCAGCTTCGGGGCCAGCTGCTTCATACTGCTTGCCATT GTGATGGGACTGGTGTTCATTTGCGTTAAAAATGGAAACATGAGATGCACCATCTGTATC 693 ATGAACACACAAATCCTGGTGTTCGCTCTAATAGCGATCATCCCAACCAATGCCGATAAG ATCTGTCTGGGCCACCACGCCGTATCCAATGGGACTAAGGTTAATACACTGACAGAGCGA GGAGTCGAAGTGGTGAACGCAACCGAGACAGTCGAAAGGACGAATATTCCCAGGATCTGC AGCAAGGGGAAGAAGACTGTTGACCTGGGACAATGTGGCCTACTGGGAACTATAACCGGC CCTCCACAATGCGACCAATTCCTGGAGTTTTCCGCTGACCTGATTATTGAACGGCGCGAA GGGAGCGACGTATGTTATCCCGGGAAATTCGTGAATGAGGAGGCTCTGCGCCAGATCCTG CGCGAGAGCGGGGGAATCGATAAGGAGGCCATGGGTTTCACCTATTCCGGAATAAGGACT AACGGCGCAACCTCAGCTTGTAGACGCAGTGGCTCTTCTTTTTATGCTGAAATGAAATGG TTATTATCAAACACGGACAACGCCGCTTTTCCCCAGATGACCAAGAGTTATAAGAACACC CGGAAATCACCTGCTCTGATAGTATGGGGAATTCATCACTCGGTGTCCACTGCGGAGCAA ACCAAACTGTACGGGAGCGGCAATAAGTTGGTTACAGTAGGAAGCTCCAATTATCAGCAA AGTTTCGTCCCCTCCCCTGGCGCCAGGCCTCAAGTGAACGGACAGTCAGGGAGAATCGAC TTCCACTGGCTGATGCTCAATCCAAACGACACCGTAACTTTCTCATTCAATGGGGCATTT ATCGCCCCAGACCGGGCCTCGTTCTTACGAGGTAAATCCATGGGGATTCAGAGCGGCGTC CAAGTGGATGCCAACTGCGAAGGCGATTGCTACCACTCTGGTGGGACAATCATCTCGAAC TTGCCGTTCCAAAACATCGATTCCCGAGCAGTGGGGAAATGCCCCAGATACGTAAAACAA AGGTCGCTGCTCCTTGCTACCGGCATGAAAAACGTCCCTGAAATCCCAAAGGGTCGTGGT CTGTTTGGCGCAATTGCTGGGTTTATTGAGAACGGCTGGGAAGGCCTGATAGACGGGTGG TATGGATTTCGTCATCAGAATGCACAGGGCGAGGGGACCGCAGCCGATTACAAGAGTACC CAGTCCGCTATTGACCAGATAACAGGGAAACTGAACCGGCTGATTGAGAAGACCAACCAG CAGTTCGAGTTGATTGACAATGAGTTCAACGAAGTCGAGAAGCAGATCGGGAATGTAATA AATTGGACAAGAGACAGCATTACAGAGGTGTGGAGCTACAATGCAGAGCTGTTAGTGGCC ATGGAGAACCAACACACGATTGACCTTGCCGATTCCGAGATGGACAAGTTGTACGAGAGA GTAAAGAGGCAGCTGAGGGAGAATGCTGAAGAAGACGGAACAGGCTGCTTTGAAATCTTC CACAAGTGTGATGATGACTGTATGGCTTCGATACGCAATAATACATACGACCATAGCAAG TATCGGGAGGAAGCCATGCAGAATAGAATTCAGATTGATCCCGTGAAACTAAGCTCGGGA TACAAGGACGTGATACTATGGTTTTCATTTGGCGCCTCCTGTTTCATCCTCCTGGCTATT GTCATGGGTTTGGTTTTTATTTGTGTTAAAAACGGCAACATGCGGTGTACTATTTGCATC 694 ATGAACACGCAGATACTGGTTTTCGCACTCATTGCAATCATCCCTACGAACGCCGACAAG ATTTGTCTGGGCCACCACGCTGTCTCTAACGGCACCAAGGTGAACACCCTGACCGAGCGC GGAGTGGAAGTGGTCAATGCGACAGAAACTGTGGAACGGACAAACATTCCACGGATCTGT AGCAAAGGCAAGAAGACAGTGGATCTGGGGCAGTGCGGCCTACTGGGCACCATCACCGGA CCTCCTCAATGCGATCAGTTTCTTGAGTTTTCCGCCGATTTGATTATAGAAAGACGGGAG GGATCCGATGTCTGCTACCCAGGCAAGTTTGTCAACGAGGAGGCCCTAAGACAGATTCTG CGGGAATCTGGCGGGATCGACAAGGAGGCAATGGGCTTCACCTACAGCGGGATCAGGACA AACGGAGCCACAAGCGCTTGTAGGCGCTCTGGTTCCTCGTTTTACGCAGAAATGAAGTGG TTACTTTCAAATACGGACAATGCGGCCTTCCCCCAGATGACCAAATCATATAAGAATACT CGCAAGAGCCCGGCATTGATTGTCTGGGGCATCCATCATTCTGTGTCTACTGCTGAACAG ACTAAACTGTATGGCTCTGGCAACAAGCTGGTGACTGTCGGAAGCAGTAACTACCAACAG AGCTTCGTGCCTAGCCCAGGGGCAAGACCCCAGGTCAACGGGCAGAGCGGGCGTATTGAC TTTCACTGGCTGATGCTGAACCCAAACGACACTGTGACATTCAGTTTCAATGGGGCCTTT ATAGCCCCTGACAGGGCCAGCTTCTTGAGGGGCAAGTCCATGGGAATACAGTCTGGTGTC CAGGTCGATGCCAATTGCGAGGGGGACTGTTATCATAGCGGCGGCACAATCATCTCAAAT CTGCCTTTCCAGAATATCGATAGTCGTGCCGTGGGAAAATGCCCCCGTTATGTAAAGCAA AGATCCTTGCTGCTAGCTACCGGGATGAAGAATGTGCCAGAAATTCCAAAGGGACGAGGC CTGTTCGGCGCTATTGCTGGCTTCATTGAGAACGGGTGGGAAGGCCTGATAGATGGGTGG TACGGGTTCAGGCACCAGAACGCACAGGGCGAGGGTACAGCTGCCGACTATAAATCTACG CAGAGCGCAATTGACCAGATCACCGGGAAGCTAAACCGTCTGATTGAAAAGACCAATCAA CAATTTGAGCTCATAGATAATGAGTTCAACGAAGTTGAAAAGCAGATTGGGAACGTCATC AACTGGACACGGGATAGTATAACGGAAGTGTGGAGTTATAACGCCGAATTACTGGTGGCG ATGGAAAACCAGCACACTATCGATTTGGCCGACTCCGAGATGGATAAGCTGTACGAGCGG GTTAAACGCCAGTTAAGGGAGAATGCTGAGGAGGATGGCACAGGTTGCTTTGAGATTTTC CATAAATGCGATGACGATTGCATGGCCTCTATTCGAAATAACACATACGACCACTCGAAG TACCGTGAGGAGGCAATGCAAAATCGAATCCAGATTGACCCAGTGAAACTCTCCAGTGGC TATAAGGATGTGATCTTGTGGTTCTCTTTTGGGGCCTCATGTTTTATTCTCCTTGCGATC GTGATGGGATTGGTTTTTATCTGTGTCAAGAATGGAAACATGAGATGCACGATCTGTATC 695 ATGAATACACAGATCTTAGTTTTTGCACTAATAGCTATCATCCCCACAAACGCCGACAAA ATTTGTCTGGGTCATCATGCTGTGTCTAACGGTACCAAGGTTAATACCCTGACCGAACGC GGGGTTGAGGTGGTTAACGCGACTGAAACGGTGGAACGCACGAATATACCCAGGATCTGT TCAAAAGGCAAAAAGACCGTTGATCTGGGTCAGTGCGGCCTTCTGGGGACAATCACCGGC CCCCCCCAGTGCGACCAGTTCCTCGAGTTTAGTGCTGATTTGATCATTGAGCGAAGAGAG GGGTCCGACGTGTGCTATCCAGGGAAGTTTGTTAATGAAGAGGCGTTGCGCCAGATCCTA CGCGAATCCGGGGGAATCGATAAGGAAGCAATGGGCTTCACCTATTCTGGCATTAGAACC AACGGAGCTACATCCGCCTGTAGAAGGAGTGGCTCGTCTTTCTATGCAGAGATGAAATGG CTGCTGTCCAACACCGACAATGCCGCTTTCCCCCAGATGACTAAAAGCTACAAGAATACC CGAAAAAGTCCAGCTCTGATCGTCTGGGGCATCCACCACTCAGTTAGTACAGCCGAACAG ACAAAGTTGTATGGCAGTGGCAACAAACTAGTCACAGTTGGCTCGTCCAACTATCAGCAG AGTTTTGTGCCCAGTCCCGGGGCACGTCCGCAGGTCAATGGACAGAGCGGCCGGATTGAT TTCCATTGGCTGATGCTGAACCCTAACGATACAGTGACATTTTCCTTCAACGGCGCGTTC ATCGCACCCGATCGCGCTTCATTCCTGAGGGGGAAGAGCATGGGGATTCAGTCGGGAGTC CAGGTTGACGCCAACTGTGAAGGAGACTGCTACCATTCAGGGGGGACAATCATCTCCAAC CTACCATTCCAGAACATTGATTCAAGAGCTGTTGGAAAGTGTCCAAGATATGTCAAGCAA AGGTCTCTATTGCTAGCTACCGGTATGAAGAATGTCCCTGAAATACCGAAGGGGAGGGGT CTGTTCGGTGCCATAGCTGGTTTTATCGAAAATGGGTGGGAGGGTCTTATCGACGGGTGG TATGGATTTCGCCACCAGAACGCCCAGGGGGAAGGCACTGCAGCTGACTATAAGTCGACT CAGTCTGCCATCGACCAGATCACCGGTAAATTAAATAGACTGATTGAGAAGACAAATCAG CAATTCGAGCTCATCGATAATGAGTTCAACGAGGTCGAGAAGCAGATTGGAAATGTGATT AACTGGACGCGCGATTCCATTACCGAGGTGTGGAGCTATAACGCGGAGTTGTTAGTGGCG ATGGAGAATCAGCATACAATTGATCTAGCGGACAGTGAAATGGACAAGCTGTACGAGAGA GTTAAACGACAGCTGCGCGAGAACGCCGAGGAGGATGGGACAGGGTGTTTTGAGATCTTC CATAAGTGTGACGATGATTGTATGGCTAGCATTAGAAATAACACTTACGATCATAGCAAA TACAGGGAGGAGGCCATGCAGAACCGAATTCAAATCGACCCCGTGAAGCTGTCTTCGGGC TACAAAGACGTTATTCTCTGGTTTAGCTTTGGTGCGTCATGCTTCATTCTGCTGGCGATT GTAATGGGGTTGGTTTTCATATGCGTTAAGAACGGCAACATGCGGTGCACTATTTGTATT

TABLE 18 Codon Optimized Sequences Encoding H10 Hemagglutinin Seq ID No. Nucleic Acid Sequence 696 5′^(7me)G_(ppp)G_(2'OMe)GGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGAGCCACCA UGUACAAAAUCGUCGUCAUUAUCGCAUUGCUGGGCGCUGUCAAGGGACUCGACAAGAU CUGUCUCGGACACCACGCGGUGGCUAACGGAACCAUCGUCAAGACCCUGACUAACGAG CAGGAAGAAGUGACCAACGCCACCGAAACUGUGGAAUCCACCGGGAUCAACAGAUUGU GCAUGAAGGGUCGGAAGCACAAGGAUCUGGGAAACUGCCACCCGAUUGGAAUGCUCAU CGGCACCCCGGCAUGCGAUCUGCAUCUGACUGGGAUGUGGGAUACCCUUAUCGAGCGG GAAAACGCGAUCGCAUACUGUUACCCCGGUGCCACCGUGAACGUGGAGGCGCUCAGAC AGAAGAUUAUGGAGUCAGGCGGCAUCAACAAGAUUUCCACGGGCUUCACCUACGGGUC CUCCAUUAACUCCGCCGGUACCACUCGGGCCUGCAUGCGGAACGGAGGGAACUCCUUU UACGCCGAGCUCAAGUGGCUUGUGUCAAAAUCCAAGGGACAGAAUUUCCCCCAAACCA CCAACACCUAUAGGAACACCGACACCGCCGAACAUCUCAUUAUGUGGGGCAUCCAUCA CCCUUCGAGCACACAGGAGAAGAAUGACCUCUACGGCACCCAGUCGCUGAGCAUCUCC GUGGGCUCAUCGACCUAUCGCAACAACUUCGUGCCUGUGGUCGGCGCCCGACCUCAAG UCAACGGACAGUCCGGACGCAUUGACUUCCAUUGGACUCUGGUGCAACCGGGAGACAA CAUCACUUUCUCCCACAACGGCGGACUGAUUGCCCCAAGCCGCGUGUCAAAGCUGAUC GGUAGAGGGCUGGGUAUUCAGUCGGAUGCUCCCAUCGAUAACAACUGCGAAUCCAAGU GCUUUUGGAGAGGCGGCUCCAUCAAUACUCGGCUGCCGUUUCAGAACCUGAGCCCGAG GACCGUGGGGCAGUGCCCAAAAUACGUGAAUCGCCGGUCACUGAUGCUGGCGACCGGA AUGAGGAACGUGCCUGAACUCAUCCAGGGACGGGGGCUGUUCGGCGCCAUCGCCGGCU UCCUGGAAAACGGAUGGGAGGGAAUGGUGGACGGUUGGUACGGCUUCCGCCACCAAAA CGCCCAGGGAACUGGACAGGCCGCCGACUACAAGUCCACACAGGCCGCAAUAGACCAG AUCACUGGGAAGCUCAACCGCCUUGUGGAAAAGACUAACACUGAAUUCGAGUCGAUCG AGUCUGAGUUCUCCGAGAUCGAACACCAGAUUGGGAACGUGAUCAACUGGACGAAGGA CUCCAUUACCGACAUCUGGACCUACCAGGCGGAACUGCUCGUGGCGAUGGAGAACCAG CACACUAUCGACAUGGCCGACUCCGAGAUGCUGAAUCUGUACGAACGCGUGCGGAAGC AACUGAGACAAAACGCUGAAGAAGAUGGAAAGGGUUGUUUCGAGAUCUACCACGCCUG CGACGACAGCUGCAUGGAAAGCAUUAGGAACAAUACCUACGACCACUCGCAGUACCGG GAGGAGGCCCUUCUGAACCGGCUGAACAUUAACCCCGUGACCUUGAGCUCCGGCUACA AGGACAUCAUCCUGUGGUUCUCGUUUGGAGCCAGCUGCUUCGUGCUGCUGGCCGUCGU GAUGGGAUUGUUCUUCUUCUGCCUGAAAAACGGAAACAUGCGCUGCACCAUCUGUAUU UGAUAAUAGGCUGGAGCCUCGGUGGCCAUGCUUCUUGCCCCUUGGGCCUCCCCCCAGC CCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGC GGCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAUCUAGOH3′ 697 ATGTACAAGATCGTCGTGATTATCGCCCTTCTGGGGGCAGTCAAGGGACTAGACAAAATAT GCCTGGGCCATCATGCAGTGGCTAACGGGACGATAGTGAAGACGCTGACCAACGAACAGGA GGAGGTCACTAACGCCACTGAGACAGTGGAGTCGACGGGCATCAATCGTTTGTGCATGAAA GGCCGGAAACACAAAGACTTAGGTAATTGTCATCCGATAGGGATGCTGATAGGCACCCCTG CATGCGACCTCCATCTCACTGGGATGTGGGACACCCTGATCGAAAGGGAAAATGCAATAGC CTATTGCTACCCCGGTGCTACCGTTAATGTCGAGGCGCTGAGACAGAAAATCATGGAATCC GGGGGAATCAACAAGATTAGCACGGGGTTTACATATGGGAGCTCAATAAATTCCGCCGGTA CTACCCGAGCATGCATGCGGAACGGCGGAAATAGTTTTTATGCCGAACTCAAGTGGCTTGT CTCCAAGTCTAAGGGACAAAATTTCCCGCAGACAACAAATACGTATCGTAACACTGATACC GCCGAGCATCTTATCATGTGGGGCATCCATCACCCTAGCTCAACGCAGGAGAAAAACGACT TGTACGGTACTCAGTCTCTATCTATCTCCGTGGGATCTTCCACCTATAGAAACAATTTTGT GCCCGTCGTAGGGGCCCGCCCTCAGGTGAATGGCCAGTCAGGCCGTATAGACTTCCATTGG ACTCTCGTACAGCCCGGGGATAATATAACCTTTAGTCATAACGGAGGCCTCATTGCTCCCA GCAGGGTTTCTAAGTTGATCGGTCGCGGGCTGGGCATTCAGTCTGATGCCCCAATTGATAA CAACTGTGAAAGCAAGTGCTTCTGGAGGGGTGGGAGTATCAATACTAGACTCCCATTCCAG AACTTGTCTCCGCGGACTGTAGGACAGTGCCCAAAGTATGTGAATCGTCGGTCTCTCATGC TGGCAACCGGTATGAGAAATGTTCCTGAGCTAATACAGGGAAGAGGACTTTTTGGAGCAAT CGCCGGATTTTTAGAAAATGGTTGGGAGGGGATGGTTGACGGATGGTACGGTTTCAGGCAC CAGAACGCCCAGGGAACCGGCCAGGCCGCGGACTACAAAAGCACACAGGCAGCCATTGATC AGATTACTGGCAAGCTGAACCGCTTAGTCGAGAAGACCAACACGGAATTTGAATCAATCGA GTCAGAATTTAGCGAAATCGAACATCAGATTGGGAACGTAATTAATTGGACAAAAGATAGC ATCACAGATATTTGGACCTACCAGGCTGAGCTACTGGTGGCTATGGAGAACCAACACACTA TTGATATGGCCGACAGCGAAATGTTAAATTTGTATGAACGGGTACGGAAGCAGCTTAGACA GAACGCAGAAGAAGATGGCAAGGGCTGCTTTGAAATTTACCACGCTTGCGATGACAGTTGC ATGGAGTCTATTAGGAACAATACATATGATCACTCTCAGTACAGAGAGGAGGCCTTGCTCA ATAGGCTGAATATCAACCCTGTCACCCTGAGCAGTGGTTATAAGGACATCATCCTGTGGTT CAGCTTTGGCGCTTCATGTTTCGTGCTGCTGGCTGTCGTCATGGGCCTTTTCTTTTTTTGT TTGAAGAACGGCAACATGCGTTGCACTATCTGCATC 698 ATGTACAAGATCGTGGTGATCATCGCTCTGCTCGGCGCCGTTAAGGGACTGGATAAGATTT GTTTAGGGCACCATGCAGTGGCAAACGGGACCATTGTCAAGACACTCACCAATGAACAGGA GGAAGTGACCAACGCGACTGAGACTGTTGAGTCCACCGGCATAAACAGGCTTTGTATGAAA GGCAGAAAGCACAAGGATTTGGGTAATTGTCACCCAATAGGAATGCTAATTGGGACTCCTG CCTGCGATCTCCACCTGACAGGCATGTGGGACACCCTGATTGAACGGGAGAATGCTATCGC ATACTGCTACCCAGGTGCAACCGTAAACGTGGAGGCCCTGCGACAGAAGATAATGGAGAGC GGAGGCATCAACAAGATCAGTACGGGATTTACCTACGGGTCTTCTATCAATTCGGCTGGCA CAACACGTGCTTGCATGAGAAACGGAGGCAACTCCTTCTACGCTGAACTCAAATGGTTGGT GAGTAAGAGTAAGGGTCAGAATTTCCCACAGACGACCAACACATACAGGAACACCGATACG GCCGAACACCTCATCATGTGGGGCATACACCACCCTAGTAGTACACAAGAGAAAAACGACC TGTATGGGACACAATCCCTTTCAATCAGTGTTGGTAGCTCGACCTACCGTAATAATTTCGT CCCTGTGGTGGGTGCTAGACCGCAGGTCAATGGCCAGTCAGGAAGGATCGATTTCCACTGG ACCCTCGTGCAGCCAGGTGATAACATTACTTTTTCTCATAATGGCGGACTAATTGCGCCTA GCAGGGTGTCAAAGCTTATTGGGAGAGGCCTAGGCATACAAAGCGACGCCCCAATCGATAA CAATTGCGAGTCGAAGTGTTTCTGGAGGGGCGGATCAATTAACACACGTCTGCCCTTCCAG AATCTGTCACCAAGGACTGTGGGCCAGTGTCCAAAGTATGTTAATCGACGTTCACTCATGC TTGCCACCGGCATGCGGAATGTGCCTGAACTGATTCAGGGCCGCGGACTTTTTGGCGCCAT TGCAGGTTTCTTGGAGAACGGGTGGGAAGGTATGGTCGACGGATGGTATGGCTTCAGACAC CAGAACGCCCAAGGAACTGGCCAGGCCGCCGATTATAAGAGCACCCAGGCTGCGATCGATC AAATTACCGGTAAACTCAACCGGCTGGTCGAGAAGACTAATACAGAGTTTGAGTCAATAGA ATCCGAGTTTTCCGAAATAGAACATCAGATCGGTAATGTAATCAACTGGACCAAGGACAGC ATCACCGACATATGGACATACCAGGCCGAACTGCTCGTCGCCATGGAGAATCAACACACGA TTGACATGGCCGATTCGGAAATGCTGAATCTGTACGAAAGGGTGCGTAAACAGTTGCGGCA GAATGCAGAAGAAGATGGAAAAGGGTGTTTTGAAATCTACCACGCCTGCGACGATAGCTGC ATGGAATCTATCCGGAATAACACCTATGACCATTCCCAATACCGAGAAGAGGCCCTGCTCA ACCGCTTGAACATTAATCCCGTTACATTGTCATCCGGATACAAGGACATCATCTTGTGGTT CTCTTTCGGGGCTTCCTGTTTTGTGCTTCTAGCAGTTGTGATGGGTCTGTTTTTCTTCTGC TTAAAGAACGGCAATATGAGATGTACTATTTGCATC 699 ATGTACAAGGTAGTGGTAATTATCGCTCTGCTAGGTGCCGTTCGTGGCTTGGACAAGATTT GTTTGGGGCACCATGCCGTAGCCAACGGAACAATTGTGAAGACACTGACTAACGAACAAGA GGAAGTAACCAACGCTACAGAAACAGTCGAATCTAAAAGTTTGGGCAAGTTATGTATGAAA GGGCGGAGTTACAACGACCTCGGAAATTGCCACCCCATCGGAATTTTAATCGGCACTCCAG CCTGCGATCTGCACTTAACAGGAACCTGGGACACCCTCATCGAACGCGAAAATGCCGTTGC ATACTGTTACCCAGGTGCGACTGTCAACGAGGAAGCGCTCCGCCAGAAGATCATGGAAAGC GGGGGGATTTCAAAAATCTCTACCGGGTTTACATACGGGACTTCCATCAACAGCGCTGGCA CCACAAAGGCCTGCATGCGCAATGGCGGTAACAGCTTCTACGCTGAGCTCAAGTGGCTGGT CAGCAAAAACAAAGGCCAGAACTTCCCCCAAACTACTAATACCTACAGAAACACAGATACC GCCGAGCACCTCATAATTTGGGGGATCCATCACCCATCTAGCACTCAGGAGAAAAACGATC TCTATGGCACACAGTCTCTCAGCATTTCAGTGGGAAGCTCGACATACCAGAATAACTTTGT TCCCGTGGTGGGCGCAAGACCACAGGTCAACGGCCAGTCCGGGAGAATTGATTTCCATTGG ACGCTGCTGCAACCTGGAGACAACATCACCTTTTCTCATAATGGCGGCCTAATTGCGCCTT CCAGAGTTAGCAAGCTGATCGGCCGGGGCCTAGGTATTCAGAGCGAGGCCCCAATTGACAA CGGTTGCGAATCAAAGTGCTTCTGGAAAGGCGGATCCATTAACACGAAGTTGCCCTTCCAG AACTTATCACCCAGAACCGTGGGGCAGTGTCCCAAATACGTGAATAAGAGGTCCCTGATGC TCGCTACCGGTATGCGGAATGTGCCTGAGATAATGCATGGAAGAGGACTGTTTGGGGCAAT CGCTGGGTTTATCGAAAACGGTTGGGAAGGGATGGTTGATGGATGGTACGGGTTTCGGCAT CAGAATGCACAGGGAACTGGTCAGGCCGCCGATTACAAATCAACGCAAGCCGCCATCGACC AGATAACTGGAAAGCTGAATAGGCTCATCGAAAAAACCAACACCGAGTTCGAATCAATTGA GTCTGAGTTCTCTGAGATCGAGCACCAAATCGGGAATATCATCAATTGGACCAAAGATAGC ATTACTGATATCTGGACATATCAGGCTGAGCTGCTGGTCGCCATGGAGAACCAGCATACAA TCGACATGGCAGACTCGGAGATGCTTAACCTGTATGAGAGGGTGCGTAAACAATTGCGACA GAATGCCGAAGAGGATGGTAAGGGTTGCTTCGAAATCTACCACGCTTGCGACGATTCTTGC ATGGAAAGTATAAGAAATAATACCTATGATCATTCACAATACCGCGAAGAGGCTTTGCTGA ACAGACTCAACATCAATCCGGTGAAGCTTTCCTCTGGGTACAAGGATATAATTCTGTGGTT TTCCTTTGGAGCTTCCTGTCTCATATTATTGGCTGTTGTTATGGGCCTCGTTTTTTTTTGC CTGAAGAACGGTAACATGCGCTGTACAATATGTATC 700 ATGTACAAAATTATCGTGATCATCGCTCTTCTGGGCGCCGTCAAAGGTCTCGATAAAATTT GCCTTGGGCACCATGCTGTGGCAAACGGAACTATTGTAAAAACTCTTACGAATGAGCAAGA AGAGGTGACCAATGCCACCGAAACCGTCGAGTCCACCGGGATCAATAGGTTGTGCATGAAG GGGCGTAAACACAAGGACCTTGGCAATTGCCATCCGATCGGCATGTTGATCGGAACACCAG CTTGTGACCTTCACTTGACCGGAACATGGGACACTCTGATCGAGCGAGAGAACGCAATTGC ATATTGCTATCCGGGAGCAACCGTGAATGTGGAGGCCCTGCGGCAGAAGATCATGGAATCC GGAGGTATCGACAAAATCTCTACCGGATTCACCTACGGATCTTCAATTAACTCCGCTGGCA CTACACGCGCTTGCATGCGAAATGGCGGTAACTCATTCTACGCCGAGCTGAAGTGGCTGGT GTCCAAGTCTAAAGGGCAGAATTTTCCGCAGACCACTAACACCTACAGAAACACTGATACC GCCGAACATCTCATTATGTGGGGAATCCACCACCCATCAAGCACTCAAGAAAAAAACGACT TGTATGGTACACAGTCACTAAGCATTTCCGTGGGCAGCTCTACCTACCGCAACAACTTTGT CCCCGTGGTTGGCGCCCGACCCCAAGTAAATGGTCAGTCCGGCAGGATCGATTTTCATTGG ACCCTGGTGCAGCCAGGGGATAACATCACTTTTAGCCATAACGGCGGCTTGATAGCGCCGT CAAGGGTGTCCAAACTGATCGGAAGAGGGCTGGGAATTCAGAGTGACGCACCCATCGATAA CAACTGCGAAAGCAAATGTTTCTGGCGGGGGGGTTCGATCAACACCCGATTACCTTTCCAG AACCTCTCCCCCAGGACTGTTGGTCAGTGCCCGAAATATGTTAATCGACGCAGCTTGATGC TCGCCACCGGGATGCGCAATGTTCCCGAGCTCATTCAGGGGCGTGGCCTCTTTGGCGCAAT AGCTGGGTTCCTCGAGAATGGTTGGGAAGGCATGGTGGATGGATGGTACGGCTTCCGGCAT CAAAACGCACAGGGCACAGGCCAGGCCGCAGATTACAAGTCTACACAGGCCGCCATTGATC AGATTACAGGTAAACTGAACAGGCTAGTGGAAAAGACCAATACCGAGTTCGAATCCATCGA ATCTGAGTTCTCAGAGATAGAGCACCAGATCGGGAACGTTATCAACTGGACCAAGGACAGC ATTACCGACATTTGGACCTACCAGGCAGAGCTCCTGGTCGCCATGGAAAATCAGCATACCA TCGACATGGCCGATTCAGAGATGCTTAACCTTTATGAGCGGGTGAGGAAACAGCTGAGGCA GAATGCAGAAGAAGATGGTAAGGGTTGCTTCGAAATTTACCATGCTTGTGATGATAGTTGT ATGGAGAGTATCCGTAACAATACTTACGATCACAGCCAGTACAGGGAAGAAGCACTCCTCA ATCGCCTCAACATCAATCCTGTAACTCTCTCGTCTGGTTACAAAGATATCATCTTATGGTT CTCTTTTGGGGCCTCATGTTTCGTGCTCCTGGCCGTGGTGATGGGCCTGTTCTTTTTCTGC TTAAAGAATGGAAATATGAGGTGCACAATCTGCATT 701 ATGTACAAGATAGTCGTTATCATCGCCTTACTCGGAGCAGTTAAAGGTTTAGATAAGATCT GCCTGGGGCACCACGCCGTCGCTAACGGCACTATTGTGAAGACGCTGACCAATGAACAAGA GGAAGTCACTAACGCAACAGAAACCGTGGAGAGCACTGGCATCAATCGCCTCTGTATGAAA GGGCGCAAGCATAAGGACCTCGGCAATTGCCACCCTATAGGCATGCTGATTGGAACGCCTG CTTGTGACCTTCACCTGACAGGGATGTGGGATACCCTAATTGAACGAGAGAACGCGATCGC ATACTGCTATCCTGGTGCCACTGTGAACGTGGAAGCCTTACGCCAAAAAATCATGGAGAGC GGAGGGATCAATAAAATCAGTACAGGTTTCACCTACGGATCCTCCATCAACAGTGCCGGTA CTACACGCGCCTGTATGAGAAACGGAGGCAACAGCTTCTATGCTGAGCTGAAATGGTTAGT GAGCAAATCCAAAGGTCAGAATTTTCCCCAGACCACAAATACTTACCGAAATACGGACACC GCCGAGCATCTGATAATGTGGGGCATCCACCATCCTAGTTCTACTCAGGAGAAAAACGACC TTTATGGAACGCAGAGCCTGTCTATAAGCGTGGGGTCTTCAACATACAGGAATAACTTTGT CCCTGTAGTGGGCGCCGGTCCTCAGGTGAATGGGCAAAGCGGCCGCATCGATTTTCACTGG ACCCTGGTTCAACCTGGAGACAATATTACGTTCAGTCACAACGGCGGCCTTATTGCCCCTT CCAGAGTCTCTAAGCTCATTGGCAGGGGACTCGGTATCCAATCCGACGCCCCTATTGACAA CAACTGCGAGTCCAAATGCTTCTGGAGGGGAGGAAGCATCAACACCCGCCTGCCATTTCAG AATCTTTCACCTCGAACCGTGGGCCAGTGTCCTAAATACGTCAATCGGAGAAGCTTGATGT TGGCCACTGGGATGCGGAACGTACCCGAGCTTATCCAAGGCAGAGGCCTTTTCGGTGCCAT CGCAGGGTTCTTGGAAAATGGCTGGGAAGGCATGGTCGATGGCTGGTATGGCTTTCGCCAT CAAAATGCTCAGGGCACGGGCCAGGCCGCTGACTACAAAAGTACACAAGCTGCCATCGATC AGATTACAGGCAAGCTCAATAGGTTGGTGGAGAAGACAAACACCGAGTTTGAGTCAATCGA GAGCGAGTTTAGCGAGATAGAGCATCAGATCGGCAACGTGATTAACTGGACTAAGGACTCT ATAACAGACATTTGGACGTACCAGGCAGAGCTCCTTGTAGCAATGGAAAATCAGCACACAA TTGACATGGCTGACTCTGAAATGCTCAACCTGTATGAGCGGGTTCGGAAGCAGCTGAGGCA GAATGCAGAGGAAGATGGTAAGGGCTGCTTTGAAATCTACCATGCCTGTGATGACAGTTGC ATGGAGAGTATTCGAAATAACACATACGATCATTCGCAGTACAGAGAGGAAGCCTTGTTGA ACCGCCTGAATATCAACCCCGTGACATTATCCTCAGGCTATAAAGACATCATCCTCTGGTT TTCGTTTGGGGCCTCGTGCTTTGTCTTGCTGGCTGTTGTCATGGGGCTGTTTTTCTTTTGT TTAAAGAACGGGAACATGCGATGCACAATCTGTATT 702 ATGTACAAGATTGTGCTGGTACTTGCACTTCTGGGTGCCGTTCACGGCCTCGACAAAATCT GCCTAGGCCACCACGCTGTGCCTAACGGGACCATTGTGAAAACCCTGACTAACGAGAAGGA GGAGGTTACCAACGCAACCGAGACTGTAGAGTCTAAGTCCTTGGATAAACTGTGCATGAAG AACCGAAACTACAAAGACCTGGGCAATTGCCATCCTATCGGGATGGTCGTCGGAACTCCAG CCTGCGATCTCCACCTAACTGGCACCTGGGACACCCTCATCGAGAGGGACAATTCAATTGC ATACTGCTATCCTGGGGCTACCGTGAGTGAAGAAGCACTGCGACAAAAAATCATGGAGTCA GGAGGGATCGACAAAATATCGACGGGATTCACATACGGCTCATCTATTAATTCAGCAGGAA CCACGAAAGCTTGTATGCGCAACGGAGGTAACTCCTTCTATAGCGAACTCAAGTGGTTAGT GTCTAAGAATAAGGGACAGAACTTTCCACAGACAACAAACACTTACCGGAACACAGACAGC GTAGAACACCTCATAATATGGGGGATCCACCACCCAAGCTCCACACAGGAGAAGAACGATT TATACGGCACTCAGTCCCTGAGCATCAGCGTCGGATCAAGCACCTACCAGAACAACTTCGT CCCCGTGGTGGGAGCTCGCCCACAGGTGAATGGCCAGAGCGGACGCATCGATTTCCACTGG ACTATGGTCCAGCCGGGTGACAACATCACCTTCTCTCACAATGGGGGGCTGATTGCTCCGA ACCGAGTGTCCAAGCTGAAAGGGAGGGGGTTAGGAATCCAGAGCGGCGCCTCGGTAGACAA CGACTGCGAGAGCAAATGTTTCTGGAAAGGTGGCTCGATTAATACCAAGCTTCCATTTCAG AATTTATCTCCTAGAACTGTCGGCCAGTGTCCAAAATACGTCAACAAAAAGTCTCTGCTCC TCGCAACAGGCATGCGGAATGTTCCCGAAGTTGCACAGGGCCGAGGCCTGTTTGGTGCCAT TGCCGGGTTTATCGAGAACGGATGGGAGGGCATGGTGGATGGATGGTACGGATTCCGACAC CAGAATGCGCAGGGGACGGGCCAAGCAGCGGATTACAAGTCCACACAAGCAGCAATTGACC AAATCACTGGCAAGTTGAATCGCCTCATAGAGAAAACTAATACAGAGTTCGAATCTATCGA AAGTGAGTTTTCCGAGATCGAACACCAGATCGGGAATGTGATCAACTGGACGAAGGATTCT ATTACTGACATATGGACCTACCAGGCCGAGCTCCTGGTGGCTATGGAAAACCAACATACAA TTGACATGGCTGACTCTGAAATGCTGAATCTGTACGAACGAGTGAGGAAGCAGCTCCGCCA AAACGCAGAGGAAGACGGAAAGGGTTGTTTTGAGATATATCACAAGTGCGACGACAACTGC ATGGAGTCCATCCGAAACAATACTTACGACCATACACAATACAGAGAGGAGGCCCTGCTGA ACCGCCTGAATATCAATCCCGTGAAGCTCAGTTCCGGTTACAAGGACGTCATTTTATGGTT CAGCTTTGGAGCGTCCTGCTTCGTGCTTCTGGCCGTCATCATGGGCCTTGTCTTCTTTTGT CTGAAAAACGGTAATATGAGATGCACCATCTGCATT 703 ATGTATAAAATTGTCGTGATCATCGCCCTGCTCGGGGCCGTCAAGGGATTGGATAAGATAT GTCTCGGTCATCATGCAGTGGCTAACGGCACGATCGTGAAGACCCTGACCAACGAGCAGGA GGAAGTGACTAATGCCACCGAAACCGTTGAGTCTACTGGTATCAATAGGCTGTGCATGAAA GGGAGAAAGCACAAGGACCTCGGCAATTGTCACCCAATCGGGATGCTCATTGGGACACCCG CATGTGACCTCCACCTGACAGGCATGTGGGATACACTGATTGAGCGCGAAAATGCCATCGC GTACTGCTACCCTGGCGCCACCGTGAATGTGGAAGCTCTGCGACAGAAAATAATGGAGAGT GGGGGGATTAATAAGATCTCTACAGGGTTTACGTACGGATCAAGTATTAACTCCGCCGGGA CTACTCGAGCATGTATGCGCAATGGCGGCAATTCCTTTTACGCCGAGCTGAAGTGGCTTGT GTCGAAGTCAAAAGGACAGAATTTTCCCCAGACAACAAACACATATCGCAATACCGATACT GCAGAACACTTGATTATGTGGGGGATTCACCACCCGTCATCTACTCAGGAGAAGAACGATC TGTATGGCACTCAGAGCCTGAGTATCTCAGTAGGCAGCAGCACCTACAGAAATAACTTCGT GCCGGTTGTCGGGGCCCGCCCACAAGTGAATGGCCAGTCAGGGCGGATCGACTTTCACTGG ACGCTGGTTCAGCCTGGAGATAACATTACGTTTAGTCACAATGGCGGGCTCATCGCGCCAA GTCGGGTATCCAAACTGATCGGCCGAGGACTTGGGATACAATCGGACGCCCCCATCGATAA CAATTGCGAATCCAAATGTTTTTGGAGAGGAGGATCCATAAATACACGACTGCCCTTTCAG AACCTGTCTCCTCGGACAGTTGGGCAGTGTCCAAAGTACGTAAACCGGAGGTCTCTCATGC TCGCGACAGGAATGCGTAATGTGCCAGAACTGATTCAGGGCCGCGGCCTCTTCGGTGCGAT CGCGGGGTTCCTCGAGAATGGTTGGGAAGGCATGGTGGACGGGTGGTATGGTTTTCGTCAT CAGAACGCTCAAGGCACTGGGCAGGCCGCCGATTACAAGTCCACGCAGGCGGCAATTGACC AAATCACCGGGAAGTTAAACCGGCTTGTCGAGAAAACCAATACCGAGTTTGAATCCATAGA GTCCGAGTTTTCCGAGATCGAGCACCAAATCGGAAACGTTATAAATTGGACCAAGGACTCT ATCACCGACATCTGGACCTACCAGGCCGAACTCCTGGTCGCCATGGAAAATCAGCACACAA TAGACATGGCAGATTCAGAGATGCTGAACCTGTACGAGCGGGTGCGTAAGCAGCTCCGGCA GAATGCGGAAGAGGACGGCAAGGGATGTTTCGAAATATACCACGCTTGTGATGATTCATGT ATGGAGTCGATCAGGAACAATACATACGACCATTCCCAGTACAGGGAAGAGGCCCTCCTGA ACAGGCTTAACATCAACCCCGTCACCCTGTCCAGCGGCTACAAGGATATTATCCTTTGGTT TTCATTCGGCGCAAGCTGCTTCGTCTTACTGGCCGTGGTAATGGGACTATTCTTTTTTTGC CTGAAAAACGGCAACATGAGGTGTACCATTTGTATT 704 ATGTACAAAATCGTGCTCGTTCTGGCCCTGCTCGGCGCCGTGCACGGCCTCGACAAGATTT GCCTGGGACATCACGCTGTGCCCAACGGTACTATTGTCAAGACACTGACGAACGAAAAAGA AGAGGTTACAAACGCTACCGAAACCGTTGAATCTAAGAGCTTGGATAAACTGTGCATGAAA AATCGCAACTATAAAGACCTCGGTAATTGTCACCCTATAGGGATGGTGGTCGGCACCCCAG CTTGCGACCTGCATTTGACAGGTACTTGGGATACTTTGATCGAACGGGATAACAGTATCGC CTACTGTTATCCGGGAGCCACGGTGTCGGAAGAGGCTCTGCGTCAGAAAATCATGGAGAGC GGCGGGATAGACAAGATCTCCACTGGCTTCACTTATGGCTCCAGCATTAATAGCGCAGGTA CAACCAAGGCTTGCATGAGAAATGGGGGGAACTCCTTCTACTCAGAACTGAAATGGCTGGT GTCCAAAAATAAGGGACAGAATTTCCCGCAGACGACAAACACCTATAGAAACACAGACTCT GTAGAGCACCTCATTATTTGGGGTATCCATCACCCAAGCTCCACCCAGGAAAAGAATGACC TGTACGGCACACAGTCCTTGAGCATTTCAGTGGGCAGCTCCACATATCAGAATAACTTTGT GCCAGTCGTTGGCGCACGACCCCAGGTGAATGGGCAGTCAGGTCGCATTGACTTCCACTGG ACTATGGTGCAGCCCGGCGATAACATTACCTTCTCCCATAACGGGGGACTGATAGCCCCCA ATAGGGTCTCTAAGCTCAAGGGTCGGGGTTTGGGCATCCAGTCCGGAGCATCCGTCGATAA CGACTGTGAGTCGAAATGCTTTTGGAAAGGTGGATCCATCAATACAAAGCTACCTTTCCAA AATTTATCCCCTCGAACGGTCGGACAGTGCCCTAAATACGTAAACAAGAAGTCACTGCTCC TCGCTACCGGCATGCGCAATGTACCTGAAGTTGCCCAAGGACGGGGGCTTTTCGGCGCAAT CGCTGGCTTCATTGAGAATGGATGGGAGGGCATGGTTGACGGCTGGTACGGCTTTAGGCAC CAGAATGCTCAGGGTACCGGTCAGGCAGCAGATTATAAAAGCACCCAGGCTGCCATCGATC AGATAACCGGGAAGTTGAACAGGCTGATCGAGAAGACCAACACTGAGTTTGAGAGCATTGA ATCGGAGTTCTCGGAAATCGAACATCAAATCGGCAATGTGATCAATTGGACTAAGGATTCT ATCACCGACATCTGGACGTACCAGGCAGAACTGTTAGTTGCAATGGAAAATCAGCATACTA TTGATATGGCAGACAGTGAGATGCTGAACCTGTACGAGCGTGTTAGAAAGCAGCTCAGACA GAACGCCGAGGAGGACGGGAAAGGATGCTTTGAAATCTATCACAAATGTGATGATAATTGC ATGGAGTCAATCAGGAATAATACATACGATCACACGCAATACAGAGAGGAGGCTCTCCTGA ACCGCCTTAATATCAACCCCGTGAAACTCAGCTCCGGATATAAAGACGTCATCCTCTGGTT TTCTTTTGGAGCAAGCTGCTTCGTGCTGCTCGCCGTTATCATGGGGTTGGTGTTCTTCTGC CTGAAGAATGGTAACATGAGATGCACCATTTGTATA 705 ATGTACAAGATTGTGCTCGTTCTGGCACTATTGGGCGCAGTGCATGGTCTGGATAAAATCT GTCTGGGTCATCACGCAGTGCCCAACGGTACTATCGTCAAAACACTAACGAACGAGAAGGA AGAAGTAACTAATGCAACGGAGACAGTGGAGTCAAAAAGTCTGGACAAGTTATGTATGAAG AACAGAAACTATAAGGATCTCGGTAATTGCCACCCCATCGGTATGGTGGTTGGGACCCCAG CCTGCGACCTTCACCTGACGGGAACCTGGGACACCCTCATCGAGCGGGACAACTCCATTGC CTATTGCTATCCTGGGGCCACCGTCTCCGAGGAGGCACTGAGGCAGAAAATTATGGAATCC GGCGGGATTGACAAGATTTCTACCGGCTTTACCTATGGCTCCTCAATCAACAGCGCTGGGA CAACTAAAGCCTGCATGAGGAACGGAGGAAATTCTTTTTACTCTGAGTTGAAGTGGTTGGT GAGCAAAAATAAGGGCCAAAATTTTCCTCAGACGACCAATACCTACCGTAATACTGACTCA GTTGAGCACCTCATCATTTGGGGAATTCATCATCCCAGCAGCACTCAGGAGAAGAATGATC TGTACGGGACCCAATCGTTGAGTATATCCGTGGGATCTAGTACTTATCAGAACAACTTTGT ACCTGTAGTGGGTGCCCGCCCACAGGTAAACGGACAGTCGGGGCGTATTGACTTTCATTGG ACAATGGTGCAGCCCGGGGATAATATCACTTTTAGCCATAATGGAGGCCTGATCGCACCAA ACCGAGTGAGCAAGCTGAAGGGTAGAGGATTGGGAATCCAGTCTGGAGCCAGCGTTGATAA CGACTGTGAGTCTAAATGCTTCTGGAAAGGGGGTAGCATAAATACCAAGCTGCCCTTCCAA AACCTGAGCCCTCGGACCGTGGGCCAGTGCCCAAAGTACGTGAATAAGAAAAGCCTCCTGC TCGCTACAGGCATGAGAAATGTGCCCGAGGTTGCACAGGGCAGAGGGCTCTTCGGCGCTAT AGCTGGATTCATTGAAAATGGCTGGGAAGGTATGGTAGATGGTTGGTACGGCTTCAGACAC CAGAATGCTCAGGGAACCGGACAGGCTGCTGATTATAAATCTACCCAGGCTGCTATCGATC AGATCACTGGGAAATTGAACCGGCTGATCGAAAAAACAAACACCGAATTCGAGAGTATTGA ATCCGAGTTTAGCGAAATTGAACATCAGATCGGCAATGTGATAAACTGGACTAAGGATAGT ATAACTGACATCTGGACATACCAAGCTGAGCTCCTGGTGGCCATGGAGAATCAACACACGA TCGACATGGCAGACTCTGAAATGTTGAACCTGTACGAGAGGGTGCGGAAGCAGCTCAGACA AAACGCTGAGGAGGACGGCAAAGGTTGCTTCGAAATCTACCATAAGTGCGACGATAACTGT ATGGAGAGTATTAGAAACAATACCTACGACCACACGCAGTATAGGGAGGAGGCTCTGTTGA ATAGGTTAAATATCAACCCTGTGAAACTATCCAGCGGCTATAAGGACGTGATTTTATGGTT CTCGTTTGGTGCCAGCTGTTTTGTCCTACTGGCAGTGATCATGGGTCTTGTTTTTTTTTGC CTGAAGAACGGCAACATGAGATGCACGATATGTATT 706 ATGTACAAGATCGTTGTGATTATCGCCCTGCTCGGCGCCGTCAAAGGATTAGACAAGATCT GTCTAGGCCATCACGCCGTTGCGAACGGAACCATCGTGAAGACCCTGACAAATGAGCAGGA AGAAGTTACCAATGCCACTGAGACCGTAGAAAGCACCGGGATCAACAGACTATGTATGAAA GGCCGCAAGCATAAGGATCTGGGAAACTGCCATCCTATCGGAATGCTCATTGGAACTCCCG CCTGTGACCTGCACCTGACCGGCATGTGGGACACACTGATTGAGCGGGAGAACGCCATCGC TTACTGTTATCCTGGTGCAACTGTGAACGTCGAAGCTTTGCGGCAGAAAATAATGGAATCG GGGGGGATTAATAAAATAAGTACCGGATTCACATATGGAAGCTCAATTAACTCCGCAGGAA CTACAAGAGCATGTATGCGAAACGGCGGCAACTCATTCTACGCTGAACTTAAGTGGCTGGT GTCTAAGTCAAAGGGGCAGAACTTTCCGCAAACCACTAATACATATCGCAATACAGACACA GCCGAGCACCTCATCATGTGGGGAATTCACCACCCAAGTAGTACCCAGGAGAAGAACGACC TGTACGGCACTCAGTCGCTTAGCATAAGTGTTGGCTCATCGACTTATCGGAATAACTTCGT CCCAGTGGTTGGTGCTCGTCCCCAAGTGAATGGTCAGTCCGGCAGAATTGATTTTCATTGG ACACTGGTGCAACCCGGTGACAACATCACTTTTAGCCATAATGGTGGTCTAATCGCCCCGT CCCGGGTGTCCAAGTTAATTGGGAGAGGTCTGGGTATCCAGAGTGATGCTCCAATCGATAA TAATTGCGAGAGTAAGTGCTTCTGGCGCGGCGGAAGTATCAACACCCGGCTCCCTTTCCAG AATCTATCACCTAGAACTGTTGGGCAGTGCCCTAAATATGTTAATCGCCGCTCACTTATGC TGGCAACCGGGATGCGAAACGTTCCAGAACTGATCCAAGGGCGGGGGCTTTTCGGGGCTAT TGCCGGGTTTTTGGAGAACGGCTGGGAAGGGATGGTCGATGGTTGGTATGGCTTCCGCCAT CAGAATGCACAGGGTACCGGCCAGGCCGCCGACTACAAGTCAACGCAGGCTGCAATTGACC AAATCACTGGGAAACTGAACCGGCTCGTTGAAAAGACTAACACTGAGTTTGAAAGCATAGA AAGTGAATTCAGTGAAATTGAGCATCAAATCGGCAACGTGATCAATTGGACCAAGGACTCA ATCACGGATATCTGGACATACCAGGCCGAGCTGCTCGTTGCGATGGAGAACCAACACACCA TCGATATGGCAGACTCTGAGATGCTAAATCTCTACGAAAGAGTGAGAAAGCAGTTGCGACA AAATGCGGAGGAGGATGGTAAGGGTTGCTTCGAAATTTACCATGCCTGCGACGACAGTTGC ATGGAATCCATTAGGAACAATACCTACGATCATTCGCAGTATAGGGAGGAGGCCCTCTTAA ACCGCCTGAACATCAACCCAGTAACCTTGAGCAGCGGGTATAAAGATATAATCCTGTGGTT TAGCTTCGGTGCCTCCTGCTTTGTTCTGCTGGCCGTAGTCATGGGTCTGTTTTTTTTCTGC CTGAAGAATGGTAATATGCGCTGCACCATTTGCATT 707 ATGTACAAGATCATTGTAATCATCGCCTTGTTGGGAGCCGTCAAAGGGCTCGATAAAATTT GCTTGGGCCATCATGCAGTCGCCAACGGGACAATAGTCAAGACGCTCACGAATGAACAGGA GGAAGTGACAAACGCCACAGAAACCGTTGAAAGTACAGGGATTAATAGGCTGTGTATGAAA GGGCGCAAACATAAGGATTTGGGCAATTGTCACCCAATAGGGATGCTTATTGGGACACCAG CTTGTGATCTCCATCTCACTGGAACATGGGACACCCTAATCGAGCGCGAAAACGCTATTGC ATATTGCTATCCGGGAGCGACGGTTAACGTGGAGGCACTCCGACAGAAAATCATGGAGAGC GGGGGGATCGACAAGATTTCCACAGGCTTTACTTACGGCTCTAGTATAAATTCCGCCGGGA CCACAAGGGCCTGTATGAGAAACGGTGGCAACAGTTTTTACGCTGAGTTAAAATGGCTCGT TAGCAAGAGCAAGGGTCAGAACTTTCCGCAGACCACAAACACATACCGGAACACCGATACA GCAGAGCATCTAATCATGTGGGGCATACATCATCCTTCCAGTACCCAGGAGAAGAACGATT TATACGGGACCCAATCCCTGAGCATCAGCGTTGGGTCATCTACTTACCGCAATAATTTTGT CCCGGTTGTGGGAGCAAGGCCCCAAGTGAATGGTCAGAGTGGCAGGATTGACTTTCACTGG ACACTGGTGCAACCTGGTGACAACATTACCTTCAGCCATAACGGAGGACTGATCGCGCCTT CACGGGTGAGCAAGCTTATTGGTAGAGGACTCGGGATCCAAAGTGATGCCCCAATCGACAA TAACTGTGAGAGCAAATGCTTTTGGCGAGGGGGATCCATCAATACACGCCTCCCCTTTCAA AACCTGAGCCCACGCACTGTGGGGCAATGCCCTAAGTACGTAAACCGCAGGTCTCTAATGC TTGCAACCGGGATGAGAAACGTTCCAGAATTAATTCAGGGACGGGGACTGTTTGGGGCGAT CGCCGGCTTTCTGGAAAATGGCTGGGAAGGGATGGTGGATGGCTGGTATGGCTTCCGGCAC CAAAATGCCCAGGGCACAGGGCAGGCTGCAGATTACAAATCAACTCAGGCTGCCATCGACC AAATCACAGGCAAGCTGAATAGGCTCGTGGAGAAAACGAACACGGAATTCGAGTCTATTGA ATCTGAGTTCTCCGAAATCGAGCACCAGATCGGGAATGTAATTAACTGGACCAAGGACTCA ATCACTGACATTTGGACCTATCAGGCAGAATTACTGGTAGCGATGGAGAACCAACACACAA TTGACATGGCAGATTCTGAAATGCTCAACCTCTATGAACGAGTGAGGAAACAGCTCCGGCA GAACGCCGAGGAGGATGGAAAGGGATGTTTCGAGATCTATCACGCATGTGACGATAGCTGT ATGGAATCTATACGGAATAACACATACGATCATTCTCAATATCGGGAGGAGGCTCTGCTTA ACCGACTCAACATAAACCCAGTCACTCTATCCAGTGGCTACAAGGATATTATCCTGTGGTT TAGCTTTGGCGCCTCGTGCTTCGTGCTTCTCGCTGTTGTCATGGGCCTGTTCTTCTTCTGT CTGAAGAACGGGAATATGCGGTGCACCATTTGCATC 708 ATGTATAAAATCGTGGTTATTATCGCATTGCTGGGTGCTGTGAAAGGCCTCGATAAAATTT GCCTCGGGCATCACGCCGTGGCCAACGGCACAATTGTGAAGACACTGACAAACGAACAGGA AGAAGTTACCAACGCTACTGAGACCGTGGAATCCACAGGTATTAATAGGCTTTGTATGAAG GGTCGGAAGCACAAAGACCTGGGGAATTGCCACCCTATCGGAATGCTCATTGGAACTCCGG CCTGTGACCTGCACCTCACAGGTATGTGGGATACTCTGATTGAGCGAGAGAACGCGATTGC CTACTGTTACCCGGGAGCAACCGTGAACGTGGAGGCGCTCCGGCAGAAGATCATGGAGTCT GGCGGCATTAACAAGATCAGTACCGGGTTCACATATGGAAGTTCAATCAATAGTGCCGGCA CTACCAGGGCATGTATGCGCAACGGAGGAAATAGCTTCTACGCGGAATTGAAATGGTTAGT CAGCAAGAGCAAGGGACAGAACTTTCCTCAGACTACGAACACTTACCGTAATACTGATACT GCCGAACATCTAATTATGTGGGGGATCCATCACCCATCCAGCACCCAGGAAAAGAACGATT TGTACGGCACCCAGTCTTTATCTATTTCCGTGGGGAGTTCGACATATAGAAATAACTTTGT GTCCGAATTCTCGGAGATTGAGCACCAGATTGGTAATGTCATCAATTGGACTAAGGACAGT ATTACTGACATCTGGACTTATCAAGCAGAGCTGCTGGTAGCTATGGAAAACCAACATACAA TCGATATGGCCGATAGCGAGATGCTGAACCTTTACGAACGAGTAAGGAAACAGCTGAGGCA GAACGCCGAAGAGGACGGCAAAGGTTGCTTTGAAATTTACCACACCTGTGACAATTCCTGT ATGGAAAGCATACGAAATAATACCTATGATCACTCCCAGTACAGAGAGGAAGCGCTCCTGA ACCGACTGAATATCAACCCCGTGAAACTGAGTTCCGGATACAAGGATATCATCCTATGGTT CTCATTCGGCGCCAGCTGTTTCGTTCTGTTAGCGGTTATAATGGGTCTGGGGTTTTTTTGT CTCAAAAATGGCAATATGCGTTGTACCATTTGTATA 715 ATGTACAAGGTTGTGGTCATCATCGCCCTGCTTGGTGCTGTGAAAGGGCTTGATAAGATAT GTTTGGGCCACCATGCCGTGGCTAACGGAACCATTGTGAAGACCTTGACCAACGAGCAGGA GGAAGTGACTAATGCCACAGAAACTGTAGAGTCTACCGGTATAAACAGGCTGTGCATGAAG GGAAGGAAGCACAAAGATCTCGGCAATTGTCATCCCATAGGCATGCTGATCGGTACCCCCG CCTGCGATCTGCACTTGACTGGCACCTGGGACACGCTGATCGAGAGGGAAAACGCTATAGC CTATTGTTACCCTGGGGCTACCGTTAATGTGGAAGCGCTGCGACAAAAGATAATGGAGAGC GGGGGCATTGATAAAATTTCAACCGGATTTACCTACGGCTCTAGTATCAACTCTGCGGGTA CTACGCGAGCATGCATGAGAAACGGGGGGAATTCCTTTTATGCAGAGCTTAAGTGGCTGGT TAGCAAGAACAAGGGTCAGAATTTCCCCCAAACTACTAACACTTACAGAAACACAGATACC GCCGAACATCTGATCATGTGGGGCATTCATCACCCATCCTCTATTCAAGAGAAGAATGACC TTTATGGCACTCAAAGCCTCTCTATCTCCGTGGGAAGCAGCACTTACCGCAATAATTTCGT GCCCGTCGTTGGGGCACGACCGCAGGTCAATGGCCAGAGTGGCAGGATCGATTTCCATTGG ACCTTAGTCCAGCCGGGCGATAATATTACCTTCAGCCATAACGGAGGACTTATTGCGCCGT CCAGAGTGTCAAAACTGATCGGGAGAGGACTCGGCATCCAGAGCGATGCTCCTATTGATAA TAATTGCGAGTCCAAGTGTTTTTGGCGTGGGGGTTCGATCAATACTAGACTACCTTTCCAG AACTTGAGCCCACGCACTGTGGGCCAGTGCCCCAAATATGTAAATAGAAGGTCCCTTATGC TCGCTACAGGTATGAGGAACGTCCCAGAACTCATTCAGGGCCGAGGTTTGTTTGGCGCAAT CGCCGGATTTCTGGAGAACGGGTGGGAGGGCATGGTCGACGGCTGGTACGGATTCCGCCAC CAGAACGCCCAAGGTACAGGTCAGGCCGCCGACTATAAGAGCACGCAGGCTGCTATAGATC AGATTACAGGAAAGCTAAACCGACTTGTGGAGAAGACAAATACAGAGTTCGAGTCAATAGA GAGTGAGTTCAGTGAGATAGAGCATCAGATCGGTAATGTCATTAACTGGACAATGGATAGC ATCACCGATATTTGGACTTATCAGGCCGAATTGCTGGTGGCTATGGAAAATCAGCACACCA TTGATATGGCAGACTCTGAGATGCTAAATCTTTACGAGCGGGTGCGAAAGCAGTTGCGGCA GAACGCAGAAGAAGACGGAAAAGGCTGCTTCGAAATATATCACGCTTGCGACGATTCCTGT ATGGAAAGCATCAGAAATAACACATATGACCACAGTCAGTATCGCGAGGAGGCTCTCCTGA ACAGACTCAATATCAATCCGGTCACCCTCTCCTCAGGTTACAAGGACATTATTCTCTGGTT TTCTTTCGGTGCGTCTTGCTTTGTGCTACTCGCTGTGGTGATGGGCTTGGTGTTCTTCTGC CTGAAGAACGGCAATATGCGGTGCACTATCTGTATC 716 ATGTACAAAATTGTGGTCATCATCGCTTTACTAGGAGCTGTGAAAGGCTTGGATAAAATTT GTCTGGGACATCATGCTGTCGCTAACGGGACCATAGTGAAAACACTCACGAACGAACAGGA GGAAGTTACCAATGCCACCGAAACGGTCGAGTCAACAGGGATTAACCGGCTGTGTATGAAG GGAAGAAAGCATAAAGATCTGGGGAACTGCCACCCTATAGGAATGTTGATAGGCACGCCTG CTTGTGACCTGCACCTGACTGGGATGTGGGATACCCTGATCGAAAGAGAGAACGCTATAGC CTATTGCTATCCCGGTGCAACAGTGAACGTGGAGGCATTGAGACAGAAAATAATGGAAAGT GGAGGGATCAATAAGATCTCAACCGGTTTTACCTATGGATCTAGTATAAATAGTGCAGGGA CCACACGTGCCTGCATGAGAAATGGGGGCAATTCTTTCTACGCGGAACTGAAGTGGCTGGT GAGCAAATCTAAGGGGCAGAATTTTCCACAGACCACGAATACATATCGTAACACAGACACC GCGGAGCACTTGATTATGTGGGGTATCCACCACCCCAGCAGCACGCAGGAAAAAAACGATC TCTACGGTACTCAGAGCCTGTCTATCTCAGTAGGCTCATCAACATACCGGAATAACTTTGT TCCAGTTGTGGGGGCCCGGCCTCAGGTGAATGGCCAGTCTGGACGCATTGATTTTCATTGG ACGCTGGTACAGCCAGGAGACAATATCACATTTAGTCATAATGGCGGTTTGATCGCCCCGA GTAGAGTGTCTAAGCTGATCGGCCGAGGCCTTGGCATTCAGTCCGACGCCCCCATCGACAA TAACTGCGAAAGCAAATGCTTTTGGAGAGGAGGTTCTATTAATACACGCCTGCCATTTCAA AACTTGAGCCCTAGAACTGTGGGTCAGTGTCCCAAGTACGTGAATCGCCGCTCCCTGATGT TAGCCACCGGGATGAGGAATGTGCCTGAGCTGATCCAGGGCAGGGGCCTATTTGGAGCCAT CGCTGGTTTCTTGGAGAATGGTTGGGAGGGTATGGTAGATGGATGGTATGGGTTTCGGCAT CAGAATGCGCAAGGCACTGGCCAGGCCGCGGATTACAAAAGCACTCAGGCTGCCATTGACC AGATAACCGGAAAACTCAACAGACTGGTTGAGAAGACCAACACTGAATTTGAGAGCATTGA GTCAGAGTTTAGCGAAATAGAACACCAGATCGGGAACGTTATTAACTGGACAAAGGACTCC ATTACGGACATATGGACATATCAGGCAGAGCTGCTAGTGGCAATGGAGAACCAACACACTA TTGACATGGCCGACTCTGAGATGCTGAACCTCTATGAGCGCGTCAGAAAGCAGCTAAGGCA GCCCGTTGTCGGTGCTGGGCCCCAAGTTAACGGCCAATCGGGACGTATCGATTTCCACTGG ACACTGGTTCAGCCAGGGGACAATATCACCTTTTCTCACAACGGAGGTCTTATAGCTCCAT CTCGTGTGTCTAAACTCATTGGACGGGGGCTTGGGATCCAAAGCGATGCCCCCATCGACAA TAATTGCGAAAGTAAGTGCTTCTGGCGGGGAGGTTCTATTAATACTAGGCTTCCTTTCCAG AACCTCTCACCACGAACAGTCGGCCAATGCCCCAAGTACGTTAATCGACGTTCACTCATGC TGGCCACGGGAATGCGCAACGTGCCCGAGCTTATCCAGGGGCGCGGATTGTTCGGCGCCAT CGCTGGCTTCTTGGAGAACGGTTGGGAGGGTATGGTCGATGGGTGGTACGGCTTTCGCCAC CAAAACGCTCAAGGGACAGGACAGGCCGCCGATTATAAGAGCACTCAGGCCGCCATAGATC AGATTACGGGCAAGCTAAACAGGCTGGTCGAGAAAACCAATACGGAATTCGAGTCCATTGA ATCAGAGTTCTCTGAGATCGAGCACCAGATCGGCAACGTAATCAACTGGACCAAAGATTCT ATCACCGATATTTGGACATATCAGGCAGAACTACTGGTCGCCATGGAAAACCAGCATACCA TCGATATGGCGGACAGTGAGATGCTTAATCTCTACGAAAGAGTACGAAAGCAGCTGCGACA AAACGCCGAGGAAGACGGTAAAGGCTGCTTCGAAATTTATCACGCGTGCGACGACTCTTGT ATGGAATCTATACGAAACAACACATACGATCACTCCCAATACCGGGAGGAGGCTCTCCTCA ATAGACTGAATATCAACCCAGTCACTTTGAGTAGTGGGTATAAGGACATTATTCTTTGGTT CTCCTTCGGGGCTTCTTGTTTTGTCCTTCTGGCAGTGGTTATGGGGCTCTTCTTTTTTTGC CTCAAGAACGGCAACATGCGCTGTACTATATGTATT 709 ATGTATAAAGTCGTTGTGATCATCGCTTTGTTGGGAGCTGTCCGGGGTTTGGATAAGATCT GCCTCGGCCATCACGCAGTAGCAAATGGAACCACTGTGAAGACCCTAACTAACGAACAAGA GGAAGTCACAAATGCCACTGAGACTGTCGAGTCTACTAGCCTGAATAAACTGTGCATGAAG GGGAGGAGGTACAAAGATCTTGGAAATTGCCACCCAATCGGAATGCTGATAGGCACCCCTG TGTGTGATCTCCATCTGACCGGAACATGGGATACCCTGATTGAGAGAGAGAATGCTACTGC ATACTGCTACCCTGGAGTCACTATCAATGAAGAGGCCCTGCGTCAAAAGATCATGGAGTCC GGGGGTATTTCTAAGATGCGCACCGGCTTTACCTACGGACCATCTATCAATTCGGCAGGTA CTACCCGGTCATGTATGCGCAATGGAGGCAACTCCTTCTATGCCGAACTGAAGTGGCTGGT CTCGGGCACTAAGGGTCAGAACTTCCCGCAGACTACTAATACATACCGAAATACCGACACT GCCGAGCACCTGATTATCTGGGGAATTCACCATCCCTCGTCCACTCAAGAGAAGAATGACC TTTATGGCACACAGAGCCTCTCGATCAGCGTGGGCTCCTCGACTTACCAGAATAACTTTGT CCCGGTAATTGGCGCTAGGCCTCAGGTGAACGGCCAGTCCGGCAGAATCGAGTTCCATTGG ACTCTGGTGCGCCCAGGCGACAATATCACATTCAGCCATAATGGGGGTCTGATCGCACCTG ACCGAGTTAGTAAACTGATTGGCAAGGGGATCGGGATCCAATCAGGGGCTGTGATCGACAA AGACTGTGAGTCAAAGTGCTTCTGGAGGGGCGGAAGCATAATTACGGAGCTGCCTTTTCAG AACCTGAGCCCAAGAACTGTTGGACAATGCCCTAAGTACGTTAAGAAGCGATCTCTCTTGT TGGCCACTGGAATGAGGAACGTGCCGGAAGTGGTTCAGGGGCGCGGCCTCTTCGGGGCTAT AGCCGGATTCATAGAAAACGGCTGGGAGGGGATGGTGGATGGCTGGTACGGCTTCAGACAC CAAAATGCGCAGGGCATCGGCCAGGCTGCTGATTACAAGTCTACCCAAACTGCGATTGATC AGATCACCGGAAAACTGAATCGACTGATCGAAAAAACTAACACTGAGTTCGAAAGCATCGA AAGTGAATTTAGCGAGATTGAACATCAGATCGGCAATGTCATAAATTGGACCAAGGATTCC ATTACAGATATTTGGACATACCAGGCCGAGCTCCTCGTGGCAATGGAAAATCAGCATACTA TTGATATGGCCGATTCGGAAATGCTGAACCTCTACGAACGTGTCCGGAAACAGCTGCGCCA GAACGCTGAGGAGGACGGAAAGGGATGCTTTGAGATTTACCACACCTGCGACAATTCTTGT ATGGAGAGTATACGCAATAATACATATGACCATTCACAATACCGCGAAGAAGCCCTTCTGA ATCGTCTCAATATCAATCCCGTCAAACTGTCCTCAGGGTATAAAGACATTATCCTATGGTT CAGTTTTGGTGCCAGCTGCTTTGTGCTGCTGGCTGTCATCATGGGGCTGGGCTTTTTTTGT CTAAAAAACGGAAACATGCGGTGCACGATCTGCATT 710 ATGTATAAGATCGTAGTGATCATTGCGCTGCTTGGCGCTGTCAAGGGCCTAGATAAGATAT GTCTCGGACACCATGCTGTTGCCAATGGGACAATTGTGAAGACTCTAACTAACGAACAGGA AGAAGTTACGAATGCTACAGAAACTGTGGAGTCCACTGGAATCAATAGACTCTGTATGAAA GGCCGGAAACACAAGGATCTGGGCAACTGCCACCCCATTGGTATGCTTATAGGAACACCTG CGTGCGATCTGCACCTCACTGGAATGTGGGATACCCTCATCGAGCGGGAGAACGCAATCGC GTACTGTTACCCCGGAGCTACGGTTAACGTCGAAGCTCTTCGGCAGAAGATCATGGAATCC GGGGGGATCAATAAGATCTCTACTGGATTCACATATGGGTCTTCAATTAACTCCGCTGGGA CGACCCGTGCCTGCATGAGGAACGGCGGTAACTCTTTCTATGCTGAGCTGAAGTGGCTGGT CAGTAAAAGTAAAGGACAGAACTTTCCGCAGACCACCAACACGTATCGGAACACTGATACA GCAGAGCACCTTATCATGTGGGGAATCCACCATCCCTCTTCTACACAAGAAAAGAATGACC TGTACGGCACTCAGAGCCTTTCAATCTCAGTGGGCAGTTCCACCTATCGAAACAACTTCGT GCCCGTGGTTGGAGCACGCCCACAGGTGAACGGCCAATCCGGGCGCATTGATTTTCATTGG ACCCTGGTTCAGCCAGGGGATAACATAACTTTCAGTCATAATGGTGGGCTCATCGCACCAA GCCGTGTTTCCAAGTTAATCGGCCGGGGGCTGGGCATCCAGAGCGACGCTCCTATCGACAA TAACTGCGAAAGTAAATGCTTCTGGCGCGGAGGTAGCATCAACACCCGACTACCCTTCCAG AATCTTAGCCCACGAACCGTGGGACAATGCCCAAAATACGTCAACCGCAGGTCTCTTATGC TAGCTACCGGTATGCGTAATGTCCCTGAGCTGATTCAGGGCCGCGGGCTTTTTGGGGCCAT TGCAGGATTTCTTGAGAATGGATGGGAAGGTATGGTTGACGGATGGTATGGCTTTAGACAC CAGAACGCGCAGGGCACTGGTCAAGCTGCAGATTACAAGTCCACACAGGCTGCTATAGACC AGATAACAGGCAAGCTGAATAGATTAGTGGAGAAAACCAACACAGAATTCGAGAGTATTGA GTCTGAATTTAGCGAGATTGAGCATCAGATTGGGAACGTGATCAATTGGACTAAAGACAGC ATCACGGACATCTGGACATACCAGGCTGAACTTTTGGTGGCCATGGAGAATCAGCACACAA TCGATATGGCAGACTCAGAGATGCTCAATTTGTATGAACGGGTGAGAAAGCAATTACGCCA GAACGCGGAAGAGGATGGCAAAGGCTGCTTTGAGATATACCACGCATGTGACGACTCATGC ATGGAATCCATCAGGAACAACACCTATGACCATTCCCAGTACCGGGAGGAAGCTCTGTTGA ACCGCCTCAACATAAACCCGGTGACACTGTCTAGCGGTTATAAAGATATCATCCTTTGGTT CTCATTCGGGGCGTCTTGTTTTGTTCTCCTTGCAGTGGTTATGGGCCTATTCTTCTTCTGC CTGAAGAATGGAAATATGAGATGTACAATCTGTATC 711 ATGTATAAAGTTGTTGTTATCATAGCGCTGCTAGGCGCTGTCAAGGGGTTAGACAAAATTT GTCTGGGCCATCACGCAGTGGCTAACGGCACAATAGTTAAGACATTGACCAATGAACAGGA GGAGGTTACAAATGCAACCGAGACCGTGGAATCAACCGGCATTAATAGACTATGTATGAAG GGCCGGAAGCATAAGGATCTGGGGAACTGCCATCCAATCGGTATGCTGATCGGCACGCCAG CTTGCGATTTGCACCTAACGGGAACCTGGGACACTTTAATCGAGAGGGAGAATGCTATAGC TTATTGCTACCCCGGCGCTACCGTTAATGTTGAGGCACTTCGGCAGAAGATCATGGAAAGC GGGGGGATCGATAAAATCAGCACAGGATTCACCTACGGGAGTTCTATCAACTCTGCCGGGA CTACACGTGCATGTATGAGAAACGGCGGTAATTCCTTCTATGCCGAGCTCAAATGGCTTGT TTCCAAGAATAAGGGCCAGAACTTCCCACAGACCACTAATACTTACAGGAATACCGACACT GCGGAGCACCTCATTATGTGGGGCATACATCACCCTTCTTCGATCCAAGAAAAGAATGACC TCTATGGTACTCAGTCCCTCAGCATATCTGTGGGGAGCAGTACTTACCGGAATAATTTCGT ACCCGTTGTGGGAGCACGCCCACAGGTGAACGGCCAGTCTGGTAGAATTGATTTCCATTGG ACTTTGGTGCAGCCGGGGGATAACATCACCTTTTCCCATAACGGGGGACTGATCGCTCCAA GCAGAGTTTCCAAACTTATTGGGAGAGGTTTAGGGATCCAGTCAGACGCCCCAATTGATAA CAACTGTGAGTCGAAGTGCTTTTGGAGAGGGGGCAGCATCAATACGCGGCTGCCTTTCCAG AACCTGTCACCCAGGACTGTCGGCCAGTGCCCAAAGTACGTGAACAGACGATCCTTGATGC TTGCCACCGGAATGCGTAATGTGCCCGAGCTGATACAGGGCCGTGGACTTTTCGGAGCCAT CGCGGGATTTCTGGAGAATGGTTGGGAAGGAATGGTCGACGGCTGGTATGGATTCCGCCAT CAAAACGCCCAAGGAACAGGCCAGGCCGCTGACTATAAAAGCACGCAGGCTGCTATTGACC AGATCACAGGTAAGCTGAACCGCCTGGTCGAAAAGACCAACACTGAATTTGAGTCCATCGA GAGCGAGTTTAGCGAAATCGAACACCAAATCGGCAATGTAATCAACTGGACCATGGACAGC ATAACCGATATTTGGACTTACCAGGCGGAATTACTGGTCGCCATGGAAAATCAGCACACAA TCGATATGGCAGACAGCGAAATGTTGAACCTCTATGAGAGAGTCAGAAAACAATTGCGGCA GAATGCTGAAGAGGATGGCAAAGGCTGCTTCGAAATCTATCACGCATGCGATGATAGTTGC ATGGAATCAATTCGGAATAATACGTATGACCATAGCCAGTACAGGGAAGAGGCCCTTCTCA ACCGACTTAATATCAATCCTGTGACACTTAGTTCTGGATATAAGGACATTATTCTCTGGTT CTCTTTTGGAGCATCATGTTTTGTGCTGCTAGCCGTGGTGATGGGCCTGGTGTTCTTTTGT CTCAAGAACGGTAACATGAGGTGTACTATATGCATC 712 ATGTATAAAATCGTGGTTATTATCGCCTTGCTAGGGGCCGTCAAAGGCCTGGACAAGATCT GTTTGGGCCACCATGCTGTGGCAAATGGCACAATTGTTAAGACACTTACCAATGAGCAGGA GGAAGTGACCAATGCTACCGAGACCGTCGAGTCTACCGGCATTAACAGGCTGTGTATGAAG GGGCGGAAACACAAAGACCTGGGAAACTGCCACCCAATCGGAATGCTGATTGGGACTCCTG CTTGCGACTTACACCTGACCGGAATGTGGGATACCCTCATAGAGAGAGAGAACGCGATAGC CTACTGTTATCCTGGGGCGACCGTGAATGTTGAGGCCCTGAGACAGAAGATTATGGAATCT GGGGGCATCAACAAAATTTCTACCGGATTTACATACGGCAGTTCCATCAACTCAGCCGGCA CAACCCGCGCGTGTATGAGAAACGGGGGGAACAGCTTTTACGCCGAGCTGAAGTGGCTGGT TTCCAAAAGCAAAGGGCAGAATTTTCCGCAGACTACGAATACCTACAGAAATACAGATACT GCCGAACACCTCATAATGTGGGGCATCCATCATCCGTCCAGTACACAGGAGAAAAATGACT TATATGGTACCCAGTCTTTATCAATTTCTGTAGGCTCCTCAACTTACCGTAACAATTTCGT GCCCGTGGTCGGAGCTCGCCCGCAGGTGAACGGCCAGAGTGGGCGCATTGACTTTCATTGG ACCCTCGTACAACCAGGCGACAACATCACTTTTTCTCATAATGGTGGTCTCATCGCCCCAA GCCGAGTCTCTAAGCTGATTGGGCGGGGTCTTGGGATCCAATCAGATGCACCTATCGATAA CAACTGCGAAAGTAAATGTTTTTGGCGTGGCGGTTCAATCAACACCCGGCTGCCGTTCCAG AACCTGAGTCCAAGAACAGTTGGTCAGTGCCCCAAGTACGTAAACCGGAGGTCTTTGATGC TGGCCACCGGAATGCGGAACGTGCCAGAACTGATCCAGGGCCGAGGCCTTTTCGGAGCCAT TGCTGGCTTTCTCGAGAACGGTTGGGAAGGAATGGTAGATGGTTGGTACGGGTTCAGACAC CAGAACGCCCAGGGCACCGGTCAGGCCGCTGATTATAAATCAACCCAGGCCGCTATAGACC AAATCACCGGCAAGCTCAACAGACTCGTGGAAAAAACGAATACGGAGTTCGAGAGCATCGA GTCAGAGTTTTCGGAAATCGAACACCAAATAGGGAATGTCATTAACTGGACTAAGGACAGC ATCACCGACATTTGGACATATCAGGCAGAATTATTAGTGGCGATGGAGAATCAGCATACCA TCGATATGGCAGACAGCGAAATGCTCAATCTGTACGAACGAGTACGCAAACAACTTCGCCA AAACGCAGAGGAGGATGGGAAGGGCTGCTTCGAGATATACCATGCATGCGATGATTCTTGC ATGGAGAGTATCCGTAACAATACATACGATCATTCCCAGTACCGAGAAGAGGCCCTGCTGA ACCGGCTGAATATCAACCCAGTTACACTCTCATCTGGCTACAAGGATATTATCCTCTGGTT CAGTTTTGGGGCATCTTGTTTCGTCCTGCTAGCTGTCGTCATGGGCCTGTTCTTTTTCTGT CTCAAAAACGGCAATATGCGGTGTACCATATGCATC 713 ATGTATAAAATTGTGGTCATTATCGCCCTTCTTGGTGCCGTGAAGGGACTTGACAAAATCT GCCTGGGCCACCACGCCGTCGCAAACGGTACTATTGTGAAAACTCTTACAAATGAGCAGGA GGAAGTGACAAATGCTACCGAGACCGTTGAAAGCACAGGTATCAACAGACTTTGTATGAAG GGACGCAAACACAAGGATCTCGGTAATTGTCATCCAATCGGTATGCTGATCGGCACTCCAG CATGTGACCTCCACCTCACCGGCATGTGGGATACTCTAATTGAGAGAGAGAACGCGATCGC TTACTGCTATCCCGGTGCGACTGTCAATGTGGAAGCCCTTCGACAGAAGATCATGGAGTCG GGCGGCATTAACAAAATTTCTACAGGTTTCACCTATGGCAGCAGTATTAACTCTGCCGGAA CAACAAGAGCCTGCATGAGGAACGGCGGAAACAGTTTCTACGCTGAACTTAAATGGTTGGT CAGCAAGAGCAAAGGCCAGAATTTCCCGCAGACCACTAACACATATCGCAACACCGACACC GCTGAGCACCTTATTATGTGGGGAATACACCACCCCTCCAGCACCCAGGAGAAGAACGACT TGTACGGTACTCAGAGCCTCTCTATCTCCGTGGGATCCTCCACATACCGCAATAACTTTGT CCCCGTGGTTGGTGCCCGCCCCCAGGTAAACGGACAGTCAGGCAGGATTGACTTCCACTGG ACCCTGGTGCAACCCGGTGACAACATTACATTCAGCCATAACGGCGGCCTAATCGCTCCCT CTCGCGTGAGTAAACTGATTGGACGGGGACTGGGGATTCAATCCGATGCTCCCATCGACAA CAATTGCGAATCCAAGTGCTTTTGGCGAGGAGGGTCCATTAACACCAGGCTGCCGTTCCAA AACTTGTCTCCCCGTACGGTGGGGCAGTGTCCCAAATACGTTAACCGCCGGTCCTTAATGC TCGCTACAGGGATGAGAAATGTGCCCGAGCTGATCCAGGGTAGAGGCCTCTTCGGTGCCAT TGCTGGATTCCTGGAGAATGGATGGGAGGGTATGGTCGACGGCTGGTACGGTTTTCGGCAT CAAAATGCTCAGGGAACAGGACAGGCGGCCGATTATAAGAGCACCCAAGCTGCTATCGATC AGATTACAGGAAAGCTGAATAGGCTGGTCGAGAAGACAAACACGGAGTTCGAAAGTATCGA ATCAGAGTTTAGCGAGATTGAACATCAGATTGGCAATGTGATTAATTGGACCAAGGACTCA ATTACCGATATCTGGACCTATCAGGCCGAGCTGCTTGTGGCCATGGAGAATCAGCATACAA TCGATATGGCCGATTCAGAAATGCTGAACCTGTACGAGCGTGTGCGTAAACAGCTGCGCCA GAATGCCGAGGAGGACGGAAAGGGGTGTTTTGAGATCTACCACGCGTGTGACGACTCATGT ATGGAGAGTATCCGGAACAATACTTACGACCATTCACAGTATCGCGAAGAGGCATTATTAA ACCGCCTTAATATCAACCCCGTGACACTCAGCAGCGGGTATAAGGACATCATTCTGTGGTT CTCATTTGGGGCCTCCTGCTTCGTTCTGCTGGCCGTGGTGATGGGGTTATTCTTTTTTTGT CTAAAGAACGGTAATATGAGGTGCACAATATGTATC 714 ATGTATAAGGTAGTAGTGATCATCGCCCTGCTGGGGGCCGTGAGAGGCCTTGATAAGATCT GTTTGGGTCACCACGCCGTTGCAAACGGGACCACTGTTAAGACCCTTACCAATGAGCAGGA GGAGGTGACGAATGCAACCGAGACCGTCGAGTCCACAAGTCTGAACAAGCTGTGTATGAAA GGGAGGAGGTATAAAGATCTGGGGAACTGCCACCCCATCGGAATGTTGATTGGAACCCCAG TCTGCGATCTGCACTTGACCGGCACCTGGGATACACTGATTGAGCGGGAGAACGCTACCGC CTACTGCTATCCCGGGGTCACTATTAATGAGGAAGCCTTGAGACAGAAGATCATGGAGAGT GGAGGGATATCCAAGATGCGGACAGGGTTCACCTACGGTCCCTCCATCAATTCCGCTGGCA CCACCCGGTCATGCATGCGCAATGGCGGCAATTCCTTTTACGCCGAGCTGAAATGGCTGGT TAGCGGGACTAAGGGACAGAACTTCCCACAAACCACTAACACCTATAGAAATACTGATACC GCGGAGCATCTGATCATATGGGGAATTCATCATCCTTCATCGACCCAGGAGAAAAACGACC TGTACGGGACTCAGTCCCTGTCCATATCCGTGGGAAGTTCCACTTATCAGAACAATTTCGT GCCTGTTATCGGAGCCCGACCTCAGGTTAACGGACAATCGGGACGGATTGAGTTCCACTGG ACTTTAGTGAGACCGGGCGACAACATCACCTTTTCTCATAACGGCGGCCTGATTGCCCCCG ATAGAGTCAGCAAATTAATCGGCAAGGGAATCGGCATACAGAGCGGGGCTGTTATTGACAA GGACTGCGAATCTAAATGCTTTTGGCGTGGTGGCTCCATTATCACTGAACTGCCCTTCCAG AATCTCAGCCCTAGAACTGTGGGCCAGTGCCCGAAGTATGTGAAAAAGAGGTCTCTTCTTC TTGCTACAGGTATGAGGAACGTCCCTGAGGTTGTCCAGGGGCGCGGCTTGTTCGGCGCTAT CGCCGGGTTCATCGAAAACGGGTGGGAGGGGATGGTGGACGGCTGGTATGGCTTTCGACAC CAGAATGCTCAAGGGATCGGGCAGGCAGCCGACTACAAATCCACCCAGACAGCTATAGACC AGATCACGGGGAAACTTAATCGTCTGATCGAAAAGACAAATACGGAGTTTGAGTCTATCGA GAATGCAGAAGAGGATGGTAAAGGGTGTTTTGAAATCTATCATGCATGCGACGATTCATGC ATGGAAAGCATCAGGAACAATACTTATGACCATTCCCAATACCGAGAGGAAGCCCTGCTGA ACAGACTGAATATTAACCCAGTGACCCTATCCAGTGGCTATAAGGATATCATCCTGTGGTT CAGCTTTGGCGCTAGCTGTTTCGTGTTACTCGCGGTCGTCATGGGACTGTTTTTTTTTTGT TTGAAGAACGGGAATATGAGATGCACAATCTGTATT 717 ATGTATAAAATCGTAGTGATTATTGCGTTGCTTGGCGCTGTGAAAGGGCTAGATAAGATCT GCCTGGGCCACCACGCCGTAGCTAACGGAACCATCGTCAAAACTTTGACTAACGAGCAGGA AGAGGTCACCAATGCTACTGAGACAGTCGAGTCTACAGGCATAAATAGACTCTGTATGAAG GGTAGAAAGCACAAGGATCTTGGGAATTGCCACCCCATTGGTATGCTGATTGGGACACCCG CCTGCGACCTGCACCTCACAGGGATGTGGGACACCTTAATTGAGCGAGAGAATGCAATCGC CTACTGTTACCCCGGGGCTACTGTTAACGTCGAAGCTCTGCGCCAGAAAATCATGGAGAGC GGGGGGATCAACAAGATCTCCACCGGCTTCACCTATGGCTCATCTATCAATTCTGCAGGCA CTACCAGAGCGTGCATGAGAAATGGAGGAAATTCCTTCTATGCGGAATTGAAATGGCTTGT GTCAAAATCTAAAGGGCAAAATTTTCCGCAGACCACCAACACCTACAGGAACACCGATACT GCAGAGCATCTGATTATGTGGGGGATTCACCACCCTTCATCCACTCAGGAAAAGAACGATC TCTATGGGACACAATCATTGTCCATTAGCGTGGGCTCTTCCACTTACAGAAACAACTTCGT GCCTGTCGTTGGGGCGCGACCGCAAGTTAATGGGCAATCCGGGCGAATTGATTTCCACTGG ACGCTGGTTCAACCTGGAGACAATATCACTTTCTCACATAATGGAGGGTTAATTGCTCCCT CCCGCGTCTCCAAACTGATTGGAAGAGGCCTGGGCATTCAGTCCGATGCCCCAATCGACAA CAATTGCGAATCCAAGTGTTTCTGGCGCGGGGGCTCAATCAATACCCGCCTGCCCTTCCAA AACCTGAGTCCCCGCACAGTGGGCCAATGCCCTAAATATGTCAACCGTCGATCCCTCATGC TTGCCACAGGCATGAGGAACGTCCCAGAGCTGATCCAGGGCCGCGGACTCTTTGGAGCTAT CGCAGGCTTTCTTGAAAACGGGTGGGAGGGCATGGTCGATGGTTGGTATGGATTTCGGCAT CAGAATGCACAAGGTACTGGACAGGCCGCTGATTACAAGTCAACCCAGGCGGCCATTGACC AGATAACCGGGAAGCTCAACCGGTTGGTCGAGAAGACTAATACTGAGTTTGAATCCATCGA AAGTGAGTTCTCTGAGATAGAACATCAGATTGGTAATGTCATAAATTGGACTAAAGATAGC ATAACGGACATTTGGACCTATCAGGCAGAATTACTGGTGGCAATGGAAAATCAACACACCA TCGACATGGCCGATTCTGAAATGCTCAACCTATACGAAAGAGTCAGAAAGCAGCTCAGACA GAACGCCGAGGAAGACGGCAAAGGGTGCTTTGAAATTTACCATGCTTGTGACGATTCTTGT ATGGAGAGTATACGCAATAACACTTATGACCATTCACAGTACCGAGAGGAGGCACTCCTGA ATCGACTGAACATCAACCCCGTCACACTGTCCTCAGGCTACAAGGATATTATCCTTTGGTT TAGTTTTGGTGCGTCGTGCTTCGTCCTCCTGGCCGTCGTGATGGGGTTATTCTTTTTTTGC TTGAAAAATGGAAATATGCGTTGCACCATCTGTATC GGACTGCGAAAGCAAATGCTTCTGGCGCGGTGGATCTATCATCACTGAATTGCCTTTCCAA AACCTGTCCCCCCGAACAGTGGGTCAGTGCCCGAAGTATGTGAAGAAGCGCAGTTTGCTAT TAGCGACTGGCATGCGGAACGTGCCTGAGGTGGTTCAGGGGCGCGGTCTCTTTGGCGCCAT CGCAGGATTTATTGAGAATGGCTGGGAGGGCATGGTCGACGGCTGGTACGGATTTAGACAT CAGAATGCTCAGGGAATTGGGCAGGCCGCCGATTACAAGAGTACCCAGACAGCAATTGACC AGATCACAGGCAAACTTAACAGGCTTATTGAGAAAACCAACACCGAGTTCGAGTCCATCGA GTCAGAGTTTAGCGAGATCGAACATCAAATCGGCAATGTGATTAATTGGACAAAAGATTCT ATTACCGATATCTGGACCTACCAGGCAGAGCTGCTGGTGGCTATGGAAAACCAGCACACCA TAGACATGGCAGACAGTGAGATGCTGAACCTATATGAGCGTGTGAGGAAACAATTGAGACA AAATGCCGAGGAAGACGGGAAGGGATGCTTCGAAATATACCACACATGTGATAACTCCTGT ATGGAATCAATTCGGAACAATACTTACGACCACAGCCAGTATCGCGAGGAAGCCTTACTTA ATCGTTTAAATATTAATCCCGTTAAGCTGAGCTCCGGTTATAAAGACATCATTCTGTGGTT CTCCTTTGGAGCCAGTTGCTTCGTTTTGCTCGCCGTTATCATGGGCCTGGGGTTTTTCTGT CTCAAGAATGGAAATATGCGATGCACCATTTGCATC 724 ATGTATAAGATTGTCGTGATTATCGCTCTCCTTGGTGCCGTTAAGGGCCTGGACAAGATCT GTCTTGGACACCACGCTGTGGCCAATGGCACTATTGTCAAAACCCTCACTAATGAGCAGGA GGAGGTCACCAACGCAACGGAGACAGTAGAAAGCACCGGGATCAACCGTCTGTGCATGAAG GGGCGGAAACATAAAGACCTCGGAAACTGCCATCCGATTGGAATGCTGATCGGGACCCCAG CTTGCGACCTCCATCTGACAGGGATGTGGGACACGCTTATCGAACGCGAGAATGCCATTGC CTATTGTTATCCTGGGGCTACTGTGAACGTAGAAGCCCTGCGTCAGAAGATTATGGAGTCC GGCGGGATCAATAAAATCAGCACAGGGTTCACCTATGGCTCTTCAATCAACAGTGCCGGAA CAACCCGCGCCTGCATGCGGAACGGCGGGAATTCCTTCTACGCCGAATTAAAGTGGTTGGT TTCTAAAAGTAAAGGGCAAAACTTCCCTCAGACCACGAACACCTATCGTAACACAGACACC GCCGAGCATCTCATCATGTGGGGGATCCACCATCCCAGCAGTACACAGGAAAAGAATGATC TGTACGGCACACAGTCGCTGTCGATCTCAGTTGGGAGTAGCACTTACCGCAACAACTTTGT GCCCGTCGTGGGGGCGAGGCCGCAGGTAAATGGGCAATCTGGACGTATAGACTTCCACTGG ACTCTAGTGCAACCCGGCGACAACATCACATTTTCTCATAACGGGGGCCTTATAGCCCCGT CTCGAGTGTCCAAACTGATTGGCCGCGGCCTCGGAATCCAGTCCGATGCCCCCATCGACAA TAATTGCGAGTCTAAATGTTTTTGGCGAGGGGGGAGCATTAACACACGGCTCCCATTTCAA AATTTGAGTCCGCGCACCGTCGGTCAGTGTCCAAAATATGTGAACAGACGCAGCTTGATGC TCGCAACGGGCATGAGAAACGTTCCTGAATTGATCCAGGGTCGGGGACTGTTTGGGGCCAT CGCAGGCTTTTTGGAGAACGGTTGGGAAGGAATGGTGGACGGATGGTACGGCTTTAGACAC CAGAACGCACAGGGAACCGGTCAGGCAGCTGACTACAAGTCAACTCAGGCCGCCATTGACC AGATCACAGGCAAGCTGAATCGACTCGTCGAGAAGACCAACACCGAATTTGAGTCTATCGA ATCAGAGTTTTCGGAGATCGAGCACCAGATCGGCAATGTGATCAATTGGACAAAGGATTCT ATCACCGATATCTGGACGTATCAGGCGGAATTGCTGGTAGCCATGGAGAATCAACACACAA TAGATATGGCCGATTCTGAGATGCTTAACCTGTACGAACGGGTCCGGAAGCAACTCCGCCA GAATGCAGAGGAGGATGGGAAGGGCTGCTTCGAGATTTACCACGCTTGTGATGACTCCTGC ATGGAGTCAATTCGAAACAACACTTACGATCACTCACAGTACCGCGAGGAAGCACTTCTTA ATAGGCTGAACATCAATCCTGTTACTCTCTCCAGCGGATATAAAGATATCATTCTGTGGTT CAGCTTCGGTGCCAGCTGCTTTGTGCTACTGGCAGTGGTCATGGGGCTCTTCTTCTTCTGC CTTAAAAATGGGAATATGCGTTGCACCATTTGCATT 725 ATGTATAAAGTGGTAGTGATCATCGCTCTGCTGGGTGCCGTGCGAGGCCTTGATAAGATCT GTCTTGGCCACCATGCAGTGGCCAACGGGACCATAGTTAAGACATTAACCAACGAACAGGA GGAGGTTACCAACGCTACCGAAACTGTCGAGAGCAAATCTCTGGGTAAGCTGTGTATGAAG GGCCGTAGCTACAATGATCTTGGTAACTGTCATCCTATCGGCATACTAATTGGGACCCCAG CCTGTGACTTGCACCTTACTGGTACTTGGGACACCTTGATAGAACGTGAAAATGCCGTGGC TTACTGTTACCCGGGCGCCACTGTGAACGAGGAGGCCCTGCGGCAGAAAATTATGGAGTCA GGTGGCATCTCTAAGATTTCAACAGGCTTCACCTACGGGACAAGTATTAATTCAGCTGGGA CTACCAAAGCCTGTATGCGAAATGGGGGTAACTCTTTTTATGCCGAGCTTAAGTGGCTGGT TTCTAAAAATAAAGGACAGAATTTTCCACAAACTACAAACACTTATCGGAACACGGACACC GCCGAGCACCTGATTATTTGGGGAATCCACCATCCATCTAGCACTCAGGAAAAAAATGATC TGTATGGTACTCAGAGCCTGAGCATTAGCGTAGGCAGCTCTACATATCAGAATAACTTTGT GCCTGTTGTAGGGGCTAGGCCTCAAGTGAACGGGCAGAGCGGTAGGATTGATTTCCACTGG ACCCTGTTGCAGCCCGGAGACAATATAACCTTCTCGCATAACGGAGGGCTGATAGCCCCGT CCAGAGTGAGTAAGCTGATCGGTAGAGGACTGGGAATTCAGAGCGAAGCCCCAATTGATAA CGGCTGCGAGAGTAAGTGCTTCTGGAAGGGCGGTAGCATTAACACGAAGTTGCCATTTCAG AATCTCAGTCCACGTACGGTGGGCCAGTGTCCCAAATACGTCAACAAACGCTCTCTGATGC TTGCTACTGGGATGAGGAATGTCCCCGAGATAATGCATGGACGCGGGTTGTTTGGCGCCAT CGCCGGGTTTATTGAGAATGGCTGGGAGGGCATGGTAGATGGATGGTACGGTTTTCGGCAT CAGAATGCCCAGGGGACCGGACAGGCTGCGGATTACAAGTCTACACAGGCAGCCATCGATC AGATCACAGGCAAGTTGAACCGACTGATCGAAAAGACAAACACAGAGTTCGAATCAATTGA GAGCGAGTTTTCCGAGATAGAGCATCAGATTGGCAACATTATTAATTGGACTAAAGATAGC ATTACCGATATATGGACCTATCAGGCAGAACTGCTCGTCGCAATGGAGAATCAGCACACTA TCGATATGGCCGATTCAGAGATGCTAAACCTGTACGAACGCGTTCGCAAGCAACTCAGACA GAATGCTGAGGAGGATGGCAAGGGTTGTTTCGAGATCTACCATGCGTGCGACGATAGTTGT ATGGAGAGCATTCGGAATAATACCTACGATCACTCCCAGTACAGGGAAGAGGCTTTGTTAA ATAGACTGAATATAAACCCTGTCAAGCTATCATCAGGTTACAAAGACATCATTCTTTGGTT CTCTTTTGGCGCTTCCTGTCTGATCCTTCTAGCCGTGGTGATGGGTCTGGTTTTCTTTTGC CTCAAAAATGGAAACATGCGTTGTACGATATGTATA 726 ATGTATAAGATAGTTGTGATAATTGCGCTGTTGGGGGCCGTGAAGGGACTCGACAAAATCT GCCTCGGCCACCATGCAGTCGCCAACGGTACTATTGTGAAAACCCTAACCAACGAACAGGA GGAGGTTACTAATGCCACCGAGACTGTCGAATCAACCGGCATCAACCGCCTCTGTATGAAA GGCCGCAAACACAAGGATCTGGGAAACTGCCACCCCATCGGCATGTTAATAGGCACCCCCG CATGCGATCTGCACCTGACAGGAATGTGGGACACCTTGATCGAGCGTGAAAACGCGATCGC TTATTGTTACCCTGGCGCGACTGTGAATGTCGAGGCTCTGAGACAGAAGATTATGGAAAGC GGTGGCATTAATAAGATTAGTACTGGATTTACTTACGGTTCCAGCATAAATTCTGCAGGGA CCACTCGCGCGTGCATGCGCAATGGTGGCAATAGTTTCTACGCTGAACTTAAGTGGCTTGT ATCTAAGTCGAAGGGACAAAATTTTCCACAGACGACCAACACATATAGGAACACAGATACA GCAGAGCACCTTATCATGTGGGGCATTCATCATCCGAGCAGTACTCAGGAGAAGAACGACC TGTACGGGACTCAGTCTTTGAGCATTAGCGTGGGAAGCAGCACTTACCGGAACAATTTTGT TCCTGTAGTGGGCGCTCGTCCTCAGGTCAATGGGCAGTCAGGACGGATAGACTTTCACTGG ACACTCGTGCAGCCCGGCGATAACATTACTTTTTCACATAATGGGGGTCTGATAGCACCAA GTCGCGTCTCTAAACTGATTGGTAGGGGCCTGGGAATTCAGTCCGACGCTCCCATCGACAA TAATTGCGAATCCAAATGCTTTTGGCGGGGAGGGTCTATTAACACCAGGTTGCCATTTCAG AATCTGTCCCCGCGGACAGTTGGCCAGTGCCCCAAGTATGTCAACCGCAGGTCCCTGATGC TCGCTACAGGAATGCGCAATGTGCCAGAGTTGATCCAGGGACGGGGCTTGTTCGGTGCAAT TGCAGGCTTTCTGGAAAACGGCTGGGAGGGGATGGTCGATGGGTGGTACGGCTTTCGCCAC CAGAACGCCCAGGGAACAGGCCAGGCCGCCGATTACAAATCTACCCAGGCTGCCATCGATC AAATTACAGGGAAATTAAACCGACTAGTCGAGAAGACCAACACTGAATTTGAATCCATTGA ATCTGAGTTTTCTGAGATAGAGCACCAGATTGGAAATGTTATTAATTGGACAAAGGATAGC ATCACAGACATATGGACATACCAAGCCGAATTGCTCGTGGCGATGGAAAACCAGCACACAA TTGATATGGCCGACAGCGAAATGCTAAACCTTTACGAGAGAGTCCGAAAGCAGCTAAGGCA GAATGCCGAGGAAGACGGTAAAGGCTGTTTCGAAATCTACCATGCATGCGACGATTCATGC ATGGAAAGTATACGCAACAATACCTATGATCATTCCCAGTACCGCGAAGAGGCCTTGCTGA ACCGACTCAACATCAACCCTGTAACCCTGAGTTCTGGGTATAAGGACATCATCCTGTGGTT TAGTTTTGGAGCATCGTGCTTTGTGCTGCTCGCTGTGGTGATGGGATTGTTCTTCTTTTGC TTAAAGAACGGCAACATGAGGTGCACCATCTGTATA 727 ATGTATAAGATTGTCGTCATCATCGCCCTACTGGGCGCGGTGAAAGGGCTAGATAAGATAT GTCTCGGGCACCATGCAGTGGCTAACGGAACAATTGTTAAAACCTTAACGAATGAACAGGA GAAGGTTACCAACGCTACTGAAACAGTTGAGTCAACTGGCCTCAACAGACTGTGCATGAAG GGTCGCAAACACAAAGATTTAGGCAACTGCCACCCCATTGGTATGTTAATCGGAACCCCAG CCTGTGATCTCCATCTGACCGGCACATGGGATACGATAATTGAGAGGGAGAATGCTATTGC CTACTGTTACCCTGGCGCCACCGTCAATGAAGAGGCCCTCAGACAGAAGATCATGGAGTCC GGGGGTATCGACAAAATTTCCACCGGTTTCACCTACGGTAGCTCCATCAATAGTGCCGGCA CTACACGCGCATGCATGCGCAATGGGGGCAACTCATTCTACGCGGAGCTAAAGTGGCTCGT TAGTAAGAGCAAAGGACAGAACTTCCCACAGACTACTAACACTTATAGGAACACTGATACG GCAGAACATTTAATTATGTGGGGCATACACCATCCTAGCTCAACGCAGGAGAAGAATGACC TATACGGTACCCAATCCCTCTCCATCAGTGTGGGGAGCTCTACTTATAGAAACAACTTCGT GCCCGTCGTAGGCGCTCGACCTCAGGTCAATGGACAGTCTGGCAGAATCGACTTCCACTGG ACTCTGGTACAACCTGGCGATAATATTACCTTTAGCCACAATGGCGGCTTAATAGCACCAT CTCGTGTGAGCAAGTTGATTGGGCGAGGATTGGGCATTCAGTCGGACGCGCCCATTGATAA CAACTGTGAATCCAAATGCTTCTGGCGTGGAGGGTCAATCAATACCCGCCTCCCCTTCCAG AACCTGTCCCCGAGGACTGTGGGCCAATGTCCCAAATATGTGAACAAGAGGTCTCTGATGC TGGCAACCGGGATGAGAAATGTGCCCGAACTGATCCAGGGACGCGGGCTATTCGGGGCTAT AGCAGGTTTTCTCGAAAATGGATGGGAGGGCATGGTGGACGGGTGGTACGGCTTTCGCCAC CAGAATGCACAGGGAACCGGCCAGGCCGCAGATTACAAATCCACCCAGGCGGCCATCGATC AGATAACCGGCAAATTGAACAGGCTGGTTGAAAAAACAAATACAGAATTCGAATCCATTGA GTCTGAGTTTAGCGAGATAGAGCACCAGATAGGCAATGTCATAAACTGGACCAAAGATTCC ATTACAGATATCTGGACATATCAGGCAGAGCTGCTCGTGGCAATGGAGAATCAGCATACTA TTGATATGGCAGACAGCGAGATGCTCAATCTGTATGAACGGGTAAGGAAACAGCTGCGTCA GAATGCTGAGGAGGACGGTAAGGGGTGTTTTGAAATATACCACGCTTGCGATGACAGTTGC ATGGAATCTATTCGCAACAATACGTACGACCACTCTCAGTACCGCGAGGAGGCCCTTCTTA ACAGGCTGAACATTAATCCCGTCACACTAAGCTCCGGTTATAAGGACATCATTCTTTGGTT TTCATTTGGCGCTAGCTGCTTCGTTCTGCTTGCCGTGGTTATGGGCCTGGTCTTTTTCTGC CTTAAGAACGGAAATATGAGGTGTACAATCTGCATT 728 ATGTACAAGATAGTGGTCATTATTGCTCTGTTGGGAGCTGTGAAAGGGCTTGATAAGATTT GCCTGGGCCACCACGCGGTGGCGAATGGGACGATCGTGAAAACTCTCACAAACGAGCAGGA AGAAGTGACTAACGCTACAGAGACCGTGGAAAGCACGGGGATCAATAGGCTGTGCATGAAG GGCCGGAAGCATAAGGATCTAGGCAACTGCCACCCAATTGGCATGCTCATCGGGACGCCCG CATGCGATCTGCACCTGACAGGGATGTGGGACACCCTTATCGAGCGTGAGAACGCCATCGC CTATTGCTACCCCGGGGCAACAGTGAATGTGGAAGCACTGAGGCAGAAGATCATGGAGAGC GGGGGAATCAACAAGATATCCACAGGCTTCACATATGGATCATCAATCAACAGCGCCGGCA CCACCCGGGCATGTATGCGGAACGGGGGCAATAGTTTCTACGCTGAGCTCAAATGGCTTGT TAGTAAGTCTAAGGGGCAGAACTTTCCACAGACTACGAATACGTACCGCAATACGGATACT GCAGAACACTTAATAATGTGGGGAATCCACCACCCAAGTTCCACCCAGGAGAAAAACGATT TGTACGGAACCCAATCCCTGTCAATATCCGTGGGAAGCTCTACCTATAGGAACAATTTCGT CCCGGTCGTGGGAGCTCGGCCACAGGTGAACGGACAGAGTGGAAGGATCGACTTCCACTGG ACGCTCGTGCAACCAGGTGATAATATCACGTTCAGTCACAACGGCGGACTGATTGCTCCAA GCCGCGTCAGCAAGCTGATAGGCCGGGGGCTGGGGATCCAGTCAGACGCCCCTATTGACAA TAATTGTGAGTCCAAATGTTTCTGGAGAGGTGGCTCTATCAATACCCGCCTTCCCTTTCAG AACTTGTCCCCACGGACAGTGGGACAGTGCCCCAAGTATGTCAATCGCAGGTCACTGATGC TGGCAACCGGGATGAGGAACGTTCCCGAACTCATTCAAGGCCGGGGTCTATTTGGCGCAAT CGCCGGCTTCCTGGAAAATGGCTGGGAAGGAATGGTGGACGGGTGGTATGGTTTCCGGCAC CAGAATGCTCAGGGCACAGGCCAGGCTGCTGATTATAAGTCTACTCAGGCAGCCATTGACC AGATCACCGGTAAGCTCAATAGATTGGTAGAAAAAACAAACACGGAGTTCGAGAGCATCGA GTCTGAATTTTCCGAGATCGAACATCAGATCGGGAACGTCATCAATTGGACCAAGGACTCT ATTACGGACATTTGGACTTACCAAGCTGAGCTCCTGGTGGCAATGGAGAACCAGCATACCA TTGATATGGCCGACTCTGAGATGCTGAACTTATACGAACGGGTGCGAAAGCAACTGAGGCA GAACGCCGAGGAGGATGGTAAGGGCTGCTTTGAGATATATCATGCCTGTGATGATTCTTGC ATGGAGAGCATCCGTAATAATACTTACGACCATAGCCAGTATCGAGAGGAAGCGCTACTCA ATCGATTAAATATCAACCCTGTGACCCTATCTTCGGGTTACAAGGACATAATTCTGTGGTT CTCATTCGGCGCATCTTGTTTCGTATTGCTCGCAGTGGTGATGGGCCTTTTTTTCTTCTGT CTGAAAAATGGTAACATGCGCTGTACTATATGCATT 729 ATGTACAAAATAGTGGTGATTATCGCCCTCCTGGGTGCTGTCAAGGGCCTGGATAAGATCT GTCTTGGCCATCACGCTGTCGCAAATGGCACTATAGTCAAAACTCTGACAAACGAGCAGGA GGAGGTGACCAACGCAACCGAGACGGTGGAATCTACTGGAATTAACAGGCTGTGTATGAAG GGTAGGAAGCATAAGGATCTAGGTAATTGCCATCCCATCGGTATGCTGATCGGAACTCCCG CGTGCGACTTACATCTCACTGGAATGTGGGACACGTTGATCGAGCGGGAGAATGCTATTGC GTACTGCTACCCCGGCGCTACGGTGAACGTCGAGGCTTTGCGTCAGAAGATCATGGAGAGC GGGGGTATCAACAAAATAAGTACCGGATTCACATACGGAAGCAGTATCAATTCCGCCGGAA CAACCCGCGCATGCATGCGGAACGGTGGTAATTCCTTCTATGCTGAACTCAAGTGGCTCGT GTCAAAGAGCAAGGGACAAAACTTTCCCCAAACGACCAATACCTATAGAAATACAGACACT GCTGAGCATCTGATCATGTGGGGCATTCACCATCCATCATCTACTCAGGAAAAAAACGACC TGTACGGTACCCAGAGCCTGTCTATTAGCGTCGGATCATCGACCTACAGGAATAACTTCGT GCCAGTCGTTGGGGCCCGCCCTCAGGTGAACGGCCAGAGCGGACGGATTGATTTTCACTGG AACTTAAGCCCAAGAACCGTGGGGCAGTGCCCTAAGTACGTTAATAGGCGGTCGCTTATGC TTGCAACAGGTATGAGGAACGTCCCGGAGCTTATCCAAGGCAGGGGACTTTTCGGAGCTAT CGCCGGTTTTTTAGAGAACGGATGGGAAGGAATGGTGGACGGTTGGTATGGATTCCGGCAC CAAAATGCTCAGGGCACCGGGCAGGCGGCTGACTACAAATCTACACAGGCGGCTATCGATC AGATTACGGGAAAGCTGAATAGGTTAGTGGAAAAAACAAACACAGAGTTTGAGAGCATCGA AAGCGAGTTTTCTGAGATAGAGCATCAGATCGGTAATGTAATCAACTGGACCAAAGACAGC ATCACAGACATATGGACGTACCAGGCTGAGCTTCTAGTCGCCATGGAAAACCAGCACACTA TTGATATGGCAGATTCTGAGATGCTTAATCTGTATGAACGAGTGCGAAAACAGCTGCGCCA GAACGCCGAAGAGGATGGGAAGGGCTGTTTCGAAATCTACCACGCCTGCGACGACTCCTGC ATGGAAAGCATTAGAAATAATACCTACGATCATTCGCAATATCGGGAAGAGGCCCTCCTGA ATCGCCTAAATATCAATCCTGTTACACTAAGCAGCGGCTACAAAGACATTATTTTATGGTT CTCCTTCGGCGCCTCCTGCTTCGTACTATTAGCCGTAGTTATGGGTCTGTTCTTCTTTTGC CTTAAGAACGGTAACATGAGATGCACAATCTGTATA 732 ATGTACAAAATTGTTGTGATCATTGCCCTCCTGGGGGCAGTGAAGGGACTGGACAAAATCT GCCTGGGTCACCACGCCGTGGCGAACGGCACCATTGTGAAGACCCTGACCAATGAACAGGA AGAGGTGACCAATGCTACCGAGACTGTAGAGAGTACAGGCATCAATAGGTTATGCATGAAA GGCCGCAAACACAAGGACTTGGGAAACTGCCACCCTATAGGCATGTTGATCGGGACGCCAG CTTGCGACTTGCACCTTACAGGAATGTGGGATACCTTGATAGAAAGGGAAAACGCTATCGC TTACTGCTACCCGGGCGCTACCGTCAATGTGGAAGCACTGCGACAGAAAATTATGGAGAGT GGTGGCATAAATAAAATATCAACTGGGTTCACATACGGAAGCTCAATCAATAGCGCGGGCA CAACACGAGCCTGCATGCGTAACGGAGGAAACAGCTTTTATGCAGAGCTCAAATGGTTAGT TTCAAAATCTAAGGGGCAGAACTTTCCTCAAACCACTAACACGTATCGGAATACCGACACA GCAGAGCACTTAATAATGTGGGGCATACATCATCCCTCAAGCACACAGGAAAAGAACGACC TGTACGGAACGCAGTCCTTATCAATCTCTGTGGGGTCCAGCACATACCGAAACAACTTTGT ACCAGTCGTGGGTGCTCGCCCACAAGTGAACGGCCAGTCTGGGCGCATCGACTTTCACTGG ACTTTGGTTCAGCCTGGTGATAATATCACCTTTAGCCATAATGGCGGACTCATAGCGCCAA GCAGGGTGTCCAAACTTATCGGACGTGGGTTGGGTATTCAGAGCGACGCACCAATCGACAA TAACTGCGAGTCAAAGTGTTTTTGGAGAGGCGGGTCAATCAACACCCGCCTGCCCTTCCAG AACCTGTCTCCCCGTACGGTGGGGCAGTGTCCAAAGTACGTGAATAGGCGGAGCCTGATGC TGGCCACAGGGATGCGCAACGTGCCTGAGCTCATTCAAGGCCGGGGCTTGTTTGGAGCCAT CGCGGGTTTTCTCGAAAACGGGTGGGAAGGGATGGTCGATGGCTGGTACGGCTTTCGGCAC CAGAATGCTCAGGGAACGGGGCAGGCTGCCGACTACAAGTCAACGCAGGCGGCCATCGATC AAATCACCGGCAAGCTCAACAGGCTCGTGGAAAAAACCAATACGGAGTTCGAAAGTATCGA AAGCGAGTTCAGCGAAATTGAGCACCAGATCGGCAATGTAATCAATTGGACTAAGGATAGC ATCACCGATATCTGGACATACCAAGCTGAGCTGTTAGTCGCCATGGAGAATCAGCATACAA TAGACATGGCTGATAGTGAAATGTTGAATCTGTACGAGAGGGTTAGGAAACAGCTGCGCCA GAATGCTGAGGAAGACGGAAAGGGCTGCTTTGAAATCTATCACGCTTGCGACGATTCCTGT ATGGAGTCCATACGAAATAATACGTACGACCATTCCCAGTACCGCGAAGAGGCTCTCCTGA ATCGGCTGAACATCAACCCTGTGACACTTAGCTCGGGCTATAAGGACATAATTTTGTGGTT CTCTTTTGGGGCATCATGTTTTGTCTTGCTGGCCGTCGTTATGGGGCTCTTCTTCTTCTGT CTAAAAAATGGAAACATGCGGTGCACCATTTGTATT 733 ATGTATAAAATCGTGGTGATCATTGCTCTGTTAGGCGCCGTGAAGGGCCTGGACAAGATTT GCCTAGGACATCATGCCGTCGCTAACGGCACTATCGTGAAGACTCTGACCAATGAGAAAGA GGAGGTGACTAACGCAACAGAAACAGTTGAGTCAACTGGCCTGAACCGGCTCTGCATGAAA GGGAGAAAGCATAAAGACCTAGGCAATTGCCATCCTATTGGTATGCTCATTGGCTCTCCCG CCTGTGACCTGCATCTTACTGGAACGTGGGACACCCTGATTGAAAGAGAAAACGCCATCGC GTATTGCTACCCGGGGGCCACCGTGAACGGAGAAGCGTTACGCCAAAAGATCATGGAGTCA GGCGGCATCGATAAGATCAGCACTGGCTTTACCTACGAAAGTAGCATCAACAGCGCTGGAA CCACCCGCGCCTGTATGAGAAACGGGGGTAATTCCTTCTATGCGGAGCTGAAATGGCTTGT GTCTAAATCCAAAGGCCAGAACTTTCCACAGACAACGAACACTTATCGGAATACTGACACA GCAGAGCATCTTATCATGTGGGGGATCCACCATCCTAGTTCCACGCAGGAGAAGAATGACC TGTATGGGACACAAAGCCTGTCTATTAGCGTGGGATCATCAACTTACAGGAACAATTTTGT CCCTGTGGTGGGCGCCAGGCCCCAGGTAAACGGACAGAGTGGACGCATCGACTTTCATTGG ACTCTCGTGCAGCCTGGGGATAATATTACCTTCAGCCATAATGGTGGCCTGATAGCACCCT CAAGAGTGTCAAAACTCATCGGTCGCGGATTGGGGATTCAATCTGACGCCCCTATAGATAA CAATTGCGAGAGCAAGTGCTTTTGGAGAGGAGGCAGCATCAACACCCGCCTTCCCTTTCAG AATCTGAGTCCCCGGACGGTTGGGCAGTGTCCTAAATATGTCAATAAGCGGTCACTCATGT TGGCAACTGGCATGCGCAACGTACCTGAGCTCATGCAGGGAAGGGGCCTCTTTGGAGCTAT TGCAGGGTTCCTGGAGAACGGCTGGGAGGGGATGGTAGACGGATGGTACGGATTCCGGCAT CAAAATGCGCAAGGCACTGGTCAAGCTGCTGATTATAAGTCCACCCAGGCCGCTATTGATC AGATTACCGGAAAGCTGAACCGGCTGGTGGAAAAGACCAATACAGAATTTGAGAGCATTGA ATCGGAGTTTAGCGAAATCGAACATCAAATTGGGAACGTCATAAACTGGACAAAAGACAGC ATCACCGATATCTGGACATACCAGGCGGAGCTGCTAGTGGCGATGGAGAATCAGCACACGA TTGATATGGCCGACTCTGAGATGCTGAATCTGTATGAGCGGGTTAGAAAGCAGCTGAGGCA AAACGCAGAAGAAGATGGTAAAGGATGCTTTGAGATCTATCATGCCTGCGATGACTCATGT ATGGAATCTATCCGTAACAATACATACGATCACAGTCAGTATCGGGAGGAAGCTCTGCTGA ATAGGCTAAACATCAATCCCGTGACCCTCTCGAGTGGCTATAAGGATATCATCTTGTGGTT CTCTTTCGGCGCCAGCTGTTTCGTGCTACTGGCCGTCGTGATGGGGCTGGTATTCTTCTGC CTGAAGAACGGTAATATGCGCTGCACCATATGTATT 734 ATGTACAAGATCGTGGTCATCATTGCACTGCTTGGCGCTGTGAAAGGATTAGACAAGATTT GCCTCGGCCACCACGCCGTCGCCAATGGGACCATCGTTAAGACATTAACAAATGAACAAGA AGAGGTAACCAACGCCACCGAGACCGTGGAGTCGACAGGCATCAACCGGTTATGCATGAAA GGGCGGAAACACAAAGATCTGGGGAACTGCCATCCAATCGGAATGCTCATTGGCACCCCAG CGTGCGATCTCCATCTCACTGGCATGTGGGATACATTAATTGAGAGGGAGAATGCAATCGC ATATTGCTACCCTGGCGCCACTGTCAACGTCGAGGCCCTGCGCCAGAAAATAATGGAATCA GGTGGCATAAACAAGATTTCCACCGGATTTACTTATGGCTCTTCCATCAACAGCGCTGGCA CCACACGGGCTTGTATGCGAAACGGGGGCAACTCATTTTATGCAGAACTGAAGTGGCTTGT CTCAAAAAGTAAGGGTCAGAACTTTCCACAGACAACAAATACATACAGGAATACCGACACT GCAGAGCATCTGATCATGTGGGGCATCCACCATCCTAGTTCGACACAGGAGAAGAACGACC TGTATGGCACCCAATCACTGAGTATCTCTGTGGGGAGTAGTACTTATCGGAACAATTTTGT GCCAGTCGTGGGCGCAAGACCACAAGTCAATGGCCAGAGTGGCCGTATCGACTTCCATTGG ACCCTGGTACAGCCTGGTGATAACATCACCTTTAGCCACAACGGAGGACTGATTGCACCGT CAAGAGTTTCAAAACTGATCGGCCGAGGCCTGGGAATCCAGAGCGACGCTCCCATCGATAA TAATTGTGAAAGTAAGTGCTTCTGGCGGGGTGGATCCATCAACACCCGTCTACCCTTTCAG AATCTGTCACCCCGGACCGTCGGACAGTGCCCAAAATACGTGAACAGGCGCAGTTTGATGT TAGCTACAGGGATGAGAAACGTGCCAGAACTGATTCAGGGACGCGGACTGTTCGGCGCCAT CGCCGGCTTCCTCGAAAACGGTTGGGAGGGTATGGTGGACGGTTGGTATGGCTTCAGGCAT CAGAACGCCCAGGGGACAGGCCAGGCCGCTGACTATAAGAGCACTCAGGCGGCTATCGACC AGATCACTGGGAAGCTCAATCGTCTCGTCGAGAAAACGAATACCGAGTTTGAGAGCATCGA AAGTGAATTCTCTGAGATAGAGCACCAGATCGGTAATGTGATCAATTGGACAAAGGACTCG ATTACTGACATCTGGACGTACCAAGCCGAGCTGCTCGTCGCCATGGAAAATCAGCATACCA TTGATATGGCTGACTCAGAGATGCTTAACTTGTACGAACGGGTCCGGAAACAACTGAGACA GAATGCCGAAGAGGACGGGAAAGGCTGTTTTGAAATCTATCACGCCTGTGATGATTCTTGT ATGGAAAGCATTAGAAACAATACATACGACCATTCACAGTACAGGGAGGAGGCTTTACTCA ATCGCCTGAACATCAATCCCGTAACATTGAGCTCTGGATATAAAGACATTATCCTCTGGTT CTCCTTTGGTGCCTCTTGTTTTGTACTCCTGGCAGTGGTTATGGGTCTCTTCTTCTTTTGT CTAAAGAACGGTAATATGAGGTGTACCATTTGCATA 735 ATGTACAAGATCGTGGTGATTATTGCCCTGTTGGGGGCCGTGAAGGGCTTGGACAAGATAT GCCTTGGTCACCATGCTGTGGCCAACGGCACTATCGTCAAAACACTGACAAACGAGCAGGA AGAGGTGACCAACGCCACGGAGACTGTAGAAAGCACCGGGATTAACCGACTATGTATGAAA GGCCGCAAACACAAGGACCTCGGGAACTGCCATCCCATCGGCATGTTAATAGGCACCCCCG CTTGCGATCTGCACCTGACAGGGATGTGGGATACCCTAATTGAGCGCGAGAACGCAATTGC CTATTGTTACCCAGGAGCCACAGTAAATGTAGAAGCTTTAAGGCAGAAGATTATGGAGAGT GGAGGGATTAACAAGATCAGCACGGGCTTCACATACGGTTCCTCCATCAATTCTGCTGGAA CCACCAGGGCATGCATGCGTAATGGGGGAAACTCATTCTACGCAGAGCTAAAGTGGCTGGT TTCCAAGTCTAAGGGACAGAACTTCCCGCAGACAACGAATACTTATCGGAACACCGACACT GCCGAACATTTAATCATGTGGGGGATCCACCACCCCAGTTCTACCCAGGAGAAAAATGATC TCTACGGTACTCAGTCCCTGTCCATCTCCGTTGGTTCCTCCACCTATCGGAATAATTTTGT CCCTGTTGTGGGAGCACGGCCACAGGTGAATGGCCAGTCCGGGAGGATAGACTTTCACTGG ACCCTTGTTCAGCCCGGGGACAATATCACTTTCTCACATAATGGGGGCCTGATTGCTCCTT CCAGAGTGAGTAAATTGATAGGCCGGGGGCTGGGCATCCAATCAGATGCACCCATTGATAA CAACTGCGAGTCCAAATGCTTCTGGCGCGGAGGCAGCATCAATACCCGACTGCCCTTCCAG AACCTGTCTCCTAGGACAGTTGGCCAGTGTCCCAAATATGTAAACCGCAGATCACTGATGC TGGCTACCGGTATGAGAAACGTCCCAGAGCTAATTCAAGGCCGAGGACTTTTTGGCGCTAT TGCAGGATTCCTTGAGAACGGGTGGGAGGGCATGGTCGACGGCTGGTACGGGTTCAGACAC CAAAACGCTCAGGGAACAGGCCAAGCCGCGGACTATAAATCAACACAAGCGGCCATTGATC AGATAACCGGCAAGCTGAATAGGCTGGTGGAAAAGACTAACACTGAGTTTGAAAGCATCGA GTCGGAATTCTCTGAGATTGAACACCAGATTGGAAATGTAATCAACTGGACAAAGGATTCC ATCACCGACATCTGGACTTATCAAGCAGAACTGTTAGTGGCCATGGAAAATCAGCATACCA TCGACATGGCCGACAGCGAGATGCTGAATCTGTACGAACGGGTTCGTAAACAGCTGAGGCA GAACGCAGAGGAGGACGGTAAGGGATGCTTTGAAATTTATCACGCTTGTGACGATAGTTGT ATGGAGAGCATTAGGAACAACACTTACGACCACTCTCAGTATAGGGAAGAAGCACTCCTTA ACAGGCTGAACATCAACCCTGTGACGCTCTCTTCCGGGTATAAAGACATCATCCTGTGGTT TTCATTTGGCGCTTCATGTTTTGTACTGCTAGCAGTGGTGATGGGTCTCTTCTTTTTTTGC CTCAAAAACGGGAACATGAGGTGCACTATTTGCATC 736 ATGTACAAGATCGTAGTGATAATCGCTCTACTAGGAGCTGTCAAAGGTCTCGATAAGATAT GTCTGGGGCACCATGCGGTAGCCAATGGAACGATCGTGAAAACACTTACTAACGAGCAGGA GGAGGTCACCAACGCCACAGAAACGGTGGAATCTACGGGGATCAACCGCTTATGCATGAAG GGGAGGAAGCATAAGGATTTGGGCAATTGCCACCCGATTGGAATGCTGATTGGGACTCCTG CTTGCGATCTGCACTTAACCGGCATGTGGGATACGCTAATAGAGCGCGAAAACGCCATCGC CTACTGTTATCCCGGCGCGACAGTAAACGTAGAGGCACTAAGACAGAAGATTATGGAGTCC GGGGGAATAAACAAGATAAGCACGGGCTTTACCTATGGATCATCCATCAATTCTGCTGGAA CAACACGCGCCTGCATGCGGAACGGAGGCAATTCTTTCTATGCAGAGCTGAAATGGCTCGT GTCCAAAAGTAAAGGTCAGAACTTCCCGCAGACTACAAACACTTATAGGAACACTGACACA GCTGAGCATCTAATCATGTGGGGTATTCACCACCCAAGTTCAACCCAAGAAAAAAATGATC TCTACGGCACGCAGTCACTTTCCATCTCTGTGGGCTCTAGCACCTACAGAAACAACTTTGT CCCAGTGGTGGGAGCTCGGCCTCAAGTGAACGGACAGTCCGGTAGGATCGATTTTCATTGG ACCCTCGTACAGCCCGGGGATAACATCACTTTTAGTCACAATGGTGGCCTGATTGCCCCCT CCAGGGTGTCTAAGTTGATTGGGCGCGGCCTAGGTATACAGAGTGACGCCCCCATAGATAA TAATTGCGAGAGCAAATGTTTCTGGAGGGGCGGAAGTATCAATACTCGGCTGCCTTTTCAG AACCTTAGCCCACGTACTGTGGGCCAGTGTCCCAAGTACGTTAATCGAAGAAGCCTGATGC TTGCAACCGGAATGAGGAACGTGCCCGAACTGATCCAAGGTCGTGGCTTATTCGGAGCCAT CGCCGGATTCCTGGAGAACGGATGGGAAGGGATGGTGGATGGGTGGTACGGGTTCCGACAC CAGAACGCCCAGGGAACAGGTCAAGCCGCCGATTACAAATCAACACAAGCGGCCATCGATC AGATTACTGGAAAACTGAACAGGTTGGTGGAGAAGACTAACACAGAGTTCGAGTCAATCGA AAGCGAATTTAGCGAGATTGAGCACCAAATCGGGAACGTGATCAACTGGACAAAGGATTCC ATTACCGACATATGGACCTACCAGGCTGAGCTGTTGGTGGCAATGGAAAATCAGCATACTA TCGATATGGCCGATTCTGAGATGCTGAATCTGTACGAGCGGGTCAGAAAGCAGCTGAGACA AAATGCTGAGGAAGACGGTAAGGGTTGTTTCGAGATCTACCATGCCTGCGACGACTCTTGC ATGGAGAGCATCAGGAACAACACATACGATCACTCCCAGTATAGAGAAGAAGCTCTGTTGA ATAGGCTTAACATCAACCCAGTGACGCTTAGTAGCGGTTACAAAGATATCATTCTGTGGTT TAGTTTTGGGGCCTCATGTTTCGTGCTTTTGGCAGTAGTTATGGGGCTGTTTTTCTTCTGT CTCAAAAATGGTAATATGCGATGCACGATTTGTATT 737 ATGTACAAAATCGTGGTCATTATCGCCCTGCTGGGCGCGGTGAAAGGCTTGGATAAAATCT GCCTCGGGCATCACGCCGTGGTGAATGGAACGATCGTGAAGACTCTGACCAACGAACAGGA AGAGGTTACCAACGCAACGGAAACAGTCGAATCAACCGGACTCAATCGTTTATGTATGAAG GGCAGAAATCACAAGGACCTTGGAAACTGCCACCCAATAGGGATGCTTATAGGAACCCCAG CTTGCGACCTGCACCTAACCGGCACCTGGGACACTCTTATTGAGAGAGAGAACGCAATTGC TTACTGTTACCCCGGCGCAACAGTGAACGAAGAGGCCCTCAGGCAGAAGATTATGGAGTCT GGAGGGATAAACAAGATATCGACCGGTTTCACCTATGGATCCTCTATCAATTCTGCAGGGA CAACCCGCGCCTGTATGAGAAATGGCGGAAACTCCTTTTATGCCGAACTGAAGTGGCTTGT TTCCAAAAGCAAAGGTCAGAACTTTCCTCAAACAACTAATACGTACAGGAACACCGATACC GCCGAGCACCTGATCATGTGGGGAATCCATCACCCTAGCAGTACCCAAGAAAAAAACGACC TATATGGTACCCAGTCCCTCAGCATCTCAGTGGGCTCATCAACCTATCAAAACAACTTCGT GCCTGTTGTCGGCGCACGACCCCAGGTGAACGGTCAAAGCGGAAGGATCGATTTCCATTGG ACCCTGGTTCAGCCCGGCGACAATATCACATTTAGTCACAATGGCGGTCTGATTGCACCTT CCCGCGTGAGTAAACTGATCGGTCGGGGGCTTGGAATTCAAAGCGACGCCCCCATCGACAA CAATTGTGAGAGCAAGTGTTTTTGGAGAGGCGGGTCAATAAACACCAGGCTGCCCTTTCAG AACCTAAGTCCCAGGACTGTAGGCCAGTGTCCCAAATACGTCAATAAGCGTTCACTAATGT TGGCCACGGGAATGAGAAACGTGCCCGAGCTGATGCAAGGCAGAGGCCTGTTCGGGGCCAT CGCGGGGTTCATCGAGAACGGTTGGGAAGGCATGGTTGATGGTTGGTATGGATTTAGGCAC CAGAACGCTCAGGGCACAGGACAGGCCGCTGACTATAAGAGTACTCAAGCCGCAATTGACC AGATCACCGGGAAGTTGAACCGACTCATCGAGAAGACGAACACAGAATTCGAGAGCATAGA GTCAGAGTTCTCGGAGATCGAACACCAAATTGGCAACGTTATCAATTGGACTAAGGACTCG ATCACTGACATCTGGACATACCAGGCTGAGCTGTTGGTGGCCATGGAAAACCAGCACACCA TAGACATGGCCGACAGCGAGATGCTGAATCTCTACGAAAGAGTTCGCAAACAGCTCAGGCA GAATGCCGAAGAAGACGGTAAAGGATGCTTTGAAATCTATCACGCTTGTGACGATTCCTGC ATGGAGAGCATCAGAAACAATACCTACGATCACAGCCAGTACCGGGAAGAAGCACTCCTGA ATAGGCTGAACATAAATCCAGTAACTCTTTCGTCCGGATACAAAGACATAATACTCTGGTT TTCGTTTGGTGCATCCTGCTTCGTGCTGCTCGCAGTGGTGATGGGGCTTGTCTTTTTCTGT TTGAAGAACGGAAATATGCGGTGCACCATATGCATC 738 ATGTACAAGATCGTTGTGATAATTGCCTTGCTGGGCGCAGTCAAAGGACTCGATAAGATCT GTCTCGGCCATCACGCCGTTGCCAATGGAACCATTGTGAAGACTCTCACTAACGAGAAAGA GGAGGTTACAAACGCTACCGAAACTGTGGAGAGTACTGGTCTGAACCGACTGTGTATGAAG GGCAGAAAGCATAAGGATCTGGGTAATTGTCACCCCATCGGAATGTTAATCGGTAGCCCAG CCTGTGATTTGCACCTTACAGGGACCTGGGATACACTCATAGAGAGGGAAAACGCCATCGC ATATTGTTATCCCGGGGCCACGGTGAACGGAGAAGCTTTACGCCAGAAGATCATGGAGTCC GGGGGGATCGATAAGATCAGCACCGGATTCACCTACGAGAGTAGTATAAACTCAGCGGGCA CCACCAGAGCGTGCATGCGGAATGGCGGCAATAGCTTTTATGCTGAGCTTAAGTGGTTGGT GTCCAAATCTAAGGGACAGAATTTCCCCCAGACCACCAATACGTACCGCAATACAGACACA GCCGAGCATTTAATCATGTGGGGAATCCACCACCCATCGTCTACCCAGGAAAAGAACGACT TGTATGGGACTCAGAGTCTTTCCATCTCCGTCGGATCCTCAACCTACCGGAACAATTTCGT GCCCGTGGTAGGGGCGCGTCCCCAAGTTAACGGCCAATCTGGCAGGATAGATTTCCATTGG ACTCTGGTGCAGCCTGGCGACAACATTACCTTCTCGCATAACGGGGGACTGATCGCCCCCT CTCGCGTTTCTAAGCTGATCGGCCGCGGTCTGGGCATCCAGTCTGACGCTCCCATTGACAA TAACTGCGAATCAAAGTGCTTTTGGAGAGGAGGGTCTATTAATACTAGGTTGCCCTTTCAG AATCTGTCCCCCCGAACCGTCGGGCAGTGTCCGAAATATGTCAACAAACGCTCATTAATGC TTGCTACTGGCATGAGGAATGTCCCTGAGTTGATGCAGGGCAGGGGGCTGTTCGGCGCCAT AGCAGGGTTTCTCGAGAACGGGTGGGAGGGCATGGTAGATGGGTGGTACGGCTTTAGGCAT CAGAATGCTCAAGGTACCGGCCAAGCCGCCGACTACAAATCCACACAGGCCGCAATTGACC AGATCACAGGTAAATTGAATCGGCTTGTGGAGAAGACCAATACTGAATTCGAAAGTATTGA ATCCGAATTTTCTGAGATAGAGCACCAAATCGGTAACGTGATCAACTGGACTAAAGATTCT ATCACCGACATTTGGACATATCAGGCGGAATTGCTGGTGGCTATGGAGAACCAGCACACGA TTGATATGGCTGACAGCGAGATGCTGAACCTTTACGAGCGAGTGCGTAAGCAACTGAGGCA GAACGCAGAGGAGGATGGTAAGGGGTGCTTCGAGATATATCACGCATGTGATGATTCATGC ATGGAGTCCATTCGCAACAATACATACGATCACAGCCAGTATCGGGAGGAAGCTCTGCTAA ACCGATTGAACATTAATCCGGTAACTTTGTCCTCCGGTTACAAGGACATTATCCTCTGGTT CTCGTTCGGGGCAAGTTGCTTCGTTCTTTTGGCAGTCGTTATGGGTCTGGTTTTTTTTTGC CTGAAGAACGGCAATATGCGCTGCACAATCTGCATC 739 ATGTATAAGATTATAGTAATCATAGCTCTTCTAGGCGCTGTCAAAGGACTAGACAAGATCT GTTTAGGCCATCATGCTGTTGCAAATGGAACAATCGTGAAAACATTAACAAACGAACAGGA AGAGGTAACAAATGCTACTGAGACAGTCGAAAGCACTGGCATCAACAGGCTGTGCATGAAG GGGCGTAAACACAAGGACCTTGGCAACTGCCATCCCATCGGAATGCTCATCGGCACCCCCG CATGCGATCTGCACCTAACCGGAACCTGGGACACTCTCATCGAGCGCGAAAACGCAATCGC CTACTGCTACCCCGGCGCTACGGTGAACGTCGAGGCGTTGCGACAGAAGATTATGGAATCA GGTGGAATCGATAAGATCTCCACTGGATTTACATACGGATCGTCTATCAACAGCGCCGGTA CAACTCGCGCCTGTATGCGTAACGGCGGAAACTCATTTTACGCCGAATTAAAGTGGCTGGT GAGCAAAAGTAAAGGGCAGAACTTTCCGCAAACAACAAATACCTATAGAAATACAGACACT GCCGAGCACCTCATTATGTGGGGTATACACCACCCTAGCAGCACGCAGGAGAAAAACGACC TCTACGGAACCCAGTCACTGAGCATCTCAGTTGGTTCCTCCACATACCGGAACAATTTCGT GCCCGTCGTGGGCGCACGCCCTCAGGTCAATGGACAGTCTGGTCGTATAGACTTTCATTGG ACGCTTGTGCAGCCAGGCGATAACATCACATTTAGCCATAACGGGGGGTTGATTGCTCCCT CACGGGTGAGCAAGCTAATAGGTAGGGGCCTCGGTATCCAGTCCGATGCACCTATTGATAA CAACTGCGAGTCTAAATGTTTTTGGCGAGGTGGGTCCATCAATACGCGGCTGCCTTTTCAG AATCTTTCTCCTCGAACTGTCGGGCAATGCCCAAAATACGTCAACCGTCGTAGTCTTATGT TGGCTACAGGGATGCGGAACGTACCGGAACTTATTCAGGGCAGAGGCCTGTTTGGTGCGAT AGCCGGCTTCCTGGAAAACGGATGGGAGGGAATGGTCGATGGATGGTACGGTTTTCGACAT CAAAATGCCCAGGGAACCGGGCAGGCAGCGGACTATAAGTCTACCCAGGCAGCCATAGACC AGATTACAGGAAAGCTCAATAGACTCGTGGAGAAAACTAACACAGAGTTTGAATCAATCGA GAGCGAGTTCAGCGAGATTGAACATCAAATCGGGAACGTGATCAACTGGACCAAAGATTCT ATCACAGACATTTGGACATACCAAGCTGAACTCCTAGTTGCCATGGAAAATCAACACACTA TCGATATGGCCGATTCAGAAATGTTGAATCTGTATGAGCGCGTGAGAAAACAACTCCGCCA AAACGCAGAAGAGGATGGCAAGGGCTGTTTTGAGATCTACCACGCCTGTGATGACTCTTGT ATGGAGTCCATTCGGAATAATACCTACGATCATAGCCAGTATCGGGAAGAGGCTCTGCTTA ACCGATTGAACATTAATCCCGTGACCTTGTCAAGCGGTTACAAAGACATAATTCTATGGTT CTCATTTGGCGCCTCCTGCTTTGTGCTGCTCGCTGTTGTCATGGGCCTCTTTTTTTTTTGT CTGAAAAATGGAAATATGCGATGTACCATCTGCATT 740 ATGTATAAAATTGTCGTGATCATAGCTCTCCTTGGGGCTGTGAAAGGCCTGGATAAGATCT GTCTGGGACACCACGCGGTGGCAAATGGCACTATCGTCAAAACCCTGACAAACGAGCAGGA GGAGGTTACTAACGCCACGGAAACGGTTGAGTCCACCGGGATTAACAGACTTTGCATGAAG GGCAGGAAACACAAGGATCTCGGTAACTGTCACCCCATTGGCATGCTGATTGGGACTCCCG CATGTGACCTTCACTTAACCGGAATGTGGGACACTCTGATCGAGCGTGAAAACGCCATTGC CTACTGTTATCCCGGGGCAACAGTGAACGTCGAGGCGTTGAGGCAAAAGATCATGGAAAGC GGCGGCATCAACAAAATCAGCACTGGGTTCACATACGGATCTAGCATTAACAGCGCCGGCA CTACACGTGCATGTATGAGGAATGGCGGCAATTCTTTTTACGCCGAACTGAAGTGGCTTGT TTCCAAATCCAAGGGTCAGAACTTTCCACAAACCACGAATACCTATCGGAATACTGACACT GCAGAGCATCTAATTATGTGGGGCATCCACCACCCCAGTTCAACTCAGGAGAAGAATGACT TGTACGGGACCCAGAGCCTGAGTATTTCTGTTGGGAGTTCAACCTACAGAAATAACTTCGT CCCTGTCGTCGGGGCTAGACCTCAAGTTAATGGTCAGTCCGGCCGTATCGACTTTCACTGG ACTCTGGTACAGCCGGGGGATAACATTACATTCTCACACAATGGGGGTCTCATCGCACCCA GCCGGGTGTCCAAACTCATTGGCCGAGGATTGGGGATCCAATCCGATGCCCCCATAGACAA CAATTGCGAGTCTAAATGCTTTTGGAGGGGCGGCTCTATAAACACACGCCTGCCATTCCAG AACCTCAGTCCCCGGACCGTCGGGCAGTGCCCAAAATATGTGAATCGAAGGAGTCTTATGC TGGCTACTGGCATGCGTAACGTGCCTGAGCTGATACAGGGAAGGGGCCTTTTCGGGGCTAT CGCCGGATTTTTAGAGAATGGATGGGAGGGGATGGTTGACGGGTGGTATGGATTTCGGCAC CAGAATGCACAGGGTACAGGACAAGCCGCCGATTACAAGTCTACCCAAGCTGCAATAGATC AGATCACCGGCAAACTCAACCGGCTTGTTGAAAAGACCAACACAGAATTCGAATCAATCGA GAGCGAGTTCTCTGAAATAGAGCATCAGATTGGCAACGTGATCAACTGGACAAAAGACTCT ATTACAGACATCTGGACTTACCAGGCTGAGTTGCTCGTGGCCATGGAGAACCAACATACAA TCGATATGGCAGACTCAGAGATGCTTAACCTGTATGAACGTGTGAGGAAGCAGCTCCGCCA GAATGCTGAAGAGGACGGAAAGGGGTGTTTTGAGATATACCATGCCTGCGACGATAGCTGC ATGGAGTCCATCAGGAACAATACGTACGATCACTCCCAATACAGAGAGGAGGCCTTGCTGA ATCGGCTTAATATCAACCCCGTCACGCTGAGTTCCGGATACAAGGATATTATACTATGGTT CTCATTTGGCGCTTCATGCTTCGTGCTCCTCGCCGTGGTGATGGGCCTGTTTTTCTTTTGC CTGAAGAACGGTAACATGAGGTGTACAATCTGCATT 741 ATGTACAAAATCGTGGTCATTATTGCCCTGCTGGGCGCCGTAAAAGGCCTCGATAAGATTT GTCTGGGACATCACGCGGTGGCTAACGGAACAATTGTTAAAACCCTGACTAACGAGCAGGA AGAAGTCACAAACGCTACGGAGACCGTGGAGAGTACCGGAATCAATCGCCTGTGCATGAAG GGCCGTAAGCACAAGGACCTGGGTAACTGCCATCCAATCGGGATGCTTATCGGCACGCCTG CTTGCGATTTGCATCTGACTGGGATGTGGGACACTCTGATCGAGCGTGAGAACGCTATAGC TTACTGCTACCCCGGAGCCACCGTCAATGTTGAAGCACTGCGTCAGAAGATCATGGAAAGC GGTGGCATCAACAAGATCTCTACCGGATTCACTTATGGCTCTTCCATAAACTCAGCAGGCA CCACACGGGCATGCATGCGGAATGGCGGCAACTCTTTCTACGCCGAACTAAAATGGCTGGT GAGTAAGAGCAAGGGGCAAAACTTTCCACAGACCACTAATACATACAGGAATACTGACACC GCAGAGCACCTCATCATGTGGGGAATCCACCATCCTTCAAGTACCCAAGAGAAAAACGATC TCTACGGGACACAGTCACTTAGTATATCCGTTGGCTCAAGCACTTACAGAAATAATTTTGT GCCCGTGGTCGGCGCCCGCCCCCAGGTTAATGGACAGAGCGGACGGATTGACTTTCATTGG ACCCTGGTCCAGCCCGGAGACAACATAACTTTTAGCCACAATGGCGGGTTGATCGCACCCA GCAGAGTTTCCAAGCTGATAGGAAGAGGGCTGGGTATCCAATCCGATGCCCCCATCGATAA CAATTGTGAGTCAAAATGCTTCTGGCGCGGAGGGTCAATCAACACACGCCTTCCCTTTCAA AACCTCTCACCTCGGACCGTGGGTCAGTGTCCGAAATATGTTAATCGACGGAGCCTGATGC TGGCCACCGGGATGCGCAACGTGCCCGAGTTGATCCAGGGTAGGGGCTTATTTGGTGCAAT CGCCGGGTTCCTGGAGAACGGATGGGAAGGCATGGTAGACGGCTGGTATGGATTCCGCCAT CAGAACGCCCAGGGGACAGGCCAGGCAGCCGATTATAAAAGCACCCAGGCTGCAATCGACC AGATCACGGGAAAGCTGAACCGGCTGGTGGAGAAGACTAATACGGAATTCGAATCTATTGA GTCTGAATTCAGTGAGATTGAGCATCAGATCGGCAACGTGATTAATTGGACTAAGGATAGC ATCACCGACATTTGGACCTATCAGGCCGAGCTGCTGGTGGCTATGGAAAATCAGCATACAA TCGACATGGCTGACTCTGAGATGCTGAACCTCTACGAGAGAGTCAGAAAACAGTTACGTCA GAACGCCGAGGAGGATGGCAAGGGGTGCTTTGAGATCTATCACGCGTGCGACGATAGTTGC ATGGAGTCAATTAGGAACAATACCTATGACCATAGTCAATACCGGGAGGAGGCCCTGTTGA ACCGGCTGAACATCAACCCTGTGACACTGTCCTCGGGGTATAAGGACATCATCCTTTGGTT CTCATTTGGAGCTAGCTGCTTCGTGTTATTGGCCGTTGTGATGGGCCTTTTCTTCTTCTGT CTCAAAAATGGAAACATGCGCTGTACCATTTGTATT 742 ATGTACAAAATCGTGCTCGTTCTGGCTCTTCTTGGGGCTGTGCACGGGCTGGATAAAATTT GCCTGGGCCACCATGCCGTCCCAAATGGCACTATTGTTAAGACTTTAACCAACGAGAAAGA GGAAGTGACTAATGCTACCGAGACAGTGGAAAGCAAAAGCCTGGACAAGCTTTGTATGAAA AATAGGAATTACAAGGATCTGGGCAATTGTCATCCAATTGGCATGGTCGTCGGCACTCCCG CCTGCGATCTGCACCTTACAGGCACGTGGGATACCCTCATCGAGCGCGATAACAGCATTGC ATATTGTTACCCAGGGGCCACGGTTAGTGAGGAAGCATTGAGACAGAAGATCATGGAGAGT GGTGGCATCGATAAGATTTCAACAGGGTTCACCTATGGATCTTCTATCAATAGTGCAGGTA CCACTAAGGCTTGCATGCGCAACGGCGGCAACTCATTTTACTCTGAGTTGAAGTGGCTCGT CAGTAAAAATAAGGGCCAGAACTTTCCGCAGACAACAAATACTTACCGAAACACGGATAGT GTGGAACACCTCATAATTTGGGGAATCCACCACCCCTCCAGCACACAGGAGAAGAACGACT TGTATGGCACTCAAAGCCTATCAATTAGCGTGGGATCATCTACTTACCAAAACAACTTTGT CCCAGTCGTGGGTGCCAGGCCACAAGTGAATGGCCAGAGTGGTCGGATTGATTTCCACTGG ACGATGGTCCAACCCGGCGATAACATTACATTTTCTCATAATGGAGGCCTCATTGCTCCTA ACAGGGTGTCTAAGCTGAAGGGCAGAGGACTCGGAATCCAATCCGGCGCCTCAGTGGATAA TGATTGTGAGAGCAAGTGTTTTTGGAAGGGGGGTTCTATCAATACTAAGCTCCCCTTCCAG AACCTGAGCCCACGCACCGTAGGACAATGCCCCAAATACGTGAACAAGAAGTCCCTGCTCC TCGCAACAGGCATGCGGAACGTTCCAGAAGTGGCACAGGGCAGGGGGTTATTTGGGGCTAT CGCTGGTTTTATTGAGAACGGATGGGAGGGGATGGTGGATGGCTGGTACGGTTTCCGCCAT CAGAACGCCCAGGGGACTGGCCAAGCGGCAGACTACAAGTCCACACAGGCAGCCATAGATC AGATAACTGGAAAGCTTAATAGGCTCATTGAGAAGACAAATACCGAGTTTGAAAGCATCGA ATCCGAATTTTCCGAGATTGAGCATCAAATTGGCAACGTAATCAACTGGACAAAGGACAGC ATTACTGACATCTGGACGTACCAGGCCGAACTGCTGGTGGCGATGGAAAACCAGCACACTA TCGATATGGCAGATAGTGAAATGCTGAACTTATATGAGCGCGTGCGAAAGCAACTGAGGCA AAACGCTGAAGAGGACGGCAAAGGGTGTTTCGAAATTTACCATAAGTGCGATGATAATTGT ATGGAGAGTATCCGGAATAACACGTATGATCATACCCAGTATCGCGAAGAAGCTCTCCTTA ACAGGCTTAATATTAATCCAGTCAAGCTAAGTTCCGGATATAAGGACGTCATTCTCTGGTT TAGTTTTGGCGCTTCCTGCTTTGTATTGCTGGCTGTGATCATGGGCCTGGTCTTCTTCTGT CTCAAGAACGGGAACATGCGATGCACCATATGCATC 743 ATGTATAAAATTGTGGTCATCATCGCTTTATTGGGAGCAGTTAAGGGGCTCGATAAGATCT GTCTGGGCCACCACGCCGTTGCAAACGGGACCATTGTGAAGACTCTCACCAATGAGCAGGA GAAAGTTACTAATGCAACAGAGACCGTCGAATCTACAGGCCTGAATCGGCTTTGTATGAAG GGACGCAAGCATAAGGACCTGGGCAATTGCCACCCTATAGGCATGCTAATTGGGACGCCGG CCTGCGACTTGCACCTCACAGGTACGTGGGACACTATCATCGAAAGGGAGAACGCTATCGC CTACTGTTACCCAGGCGCTACCGTGAACGAGGAAGCGCTGAGACAGAAAATCATGGAATCC GGTGGAATCGATAAGATATCTACTGGCTTTACTTACGGCTCATCCATTAATTCCGCTGGCA CCACTCGCGCCTGTATGCGGAACGGCGGCAATTCCTTCTACGCTGAACTTAAATGGCTCGT GTCCAAGAGCAAAGGCCAGAACTTTCCACAGACCACCAATACTTATAGAAATACAGACACG GCCGAGCACCTGATCATGTGGGGGATCCATCACCCTAGTAGTACACAGGAGAAAAATGACT TATACGGCACCCAATCCCTTAGTATATCTGTTGGGTCAAGCACGTACAGAAACAATTTCGT GCCTGTAGTGGGCGCCAGGCCACAGGTCAACGGGCAGTCAGGCAGGATTGATTTCCATTGG ACACTGGTGCAACCTGGTGATAATATCACTTTCTCCCACAACGGCGGTTTAATTGCTCCCA GCAGAGTAAGTAAGCTCATCGGCCGAGGACTCGGCATTCAGAGCGACGCACCCATAGATAA TAACTGCGAATCTAAATGTTTTTGGAGGGGGGGCTCTATCAATACACGCCTCCCTTTTCAG AACCTGTCTCCTAGGACTGTAGGGCAGTGCCCCAAGTACGTAAACAAAAGATCGCTGATGT TAGCCACCGGGATGCGGAACGTCCCTGAGCTCATTCAGGGAAGGGGCCTGTTCGGAGCCAT TGCAGGGTTCTTGGAGAATGGATGGGAAGGAATGGTTGACGGGTGGTACGGGTTCCGACAT CAGAATGCCCAAGGCACCGGACAGGCCGCTGACTACAAAAGCACCCAGGCAGCCATAGACC AGATTACCGGCAAACTAAATCGTTTAGTGGAGAAGACCAATACCGAATTTGAATCCATAGA GAGCGAATTCAGCGAGATAGAGCATCAAATCGGCAATGTGATTAACTGGACAAAAGATTCC ATAACCGACATTTGGACTTATCAGGCCGAGTTGCTAGTCGCAATGGAGAATCAGCATACAA TCGACATGGCTGACTCTGAGATGTTGAATCTGTACGAGAGGGTTCGGAAGCAGCTGCGGCA GAACGCCGAGGAAGACGGGAAAGGGTGTTTTGAGATCTACCATGCGTGTGATGATAGCTGT ATGGAAAGCATTCGCAATAACACCTATGACCACTCACAGTATCGGGAAGAGGCGTTGTTAA ACAGGCTGAACATCAACCCAGTAACACTGTCTAGCGGTTATAAGGACATAATATTGTGGTT CTCCTTTGGTGCAAGCTGCTTTGTCTTGCTGGCGGTCGTGATGGGGCTGGTGTTCTTTTGT CTGAAAAACGGTAACATGAGGTGTACTATTTGTATC 744 ATGTATAAGATCGTTCTCGTGTTGGCTCTACTGGGTGCCGTCCATGGTTTGGACAAGATCT GCCTGGGCCACCATGCAGTGCCAAACGGTACCATAGTGAAAACCTTGACTAATGAAAAAGA AGAGGTGACTAATGCCACCGAGACCGTGGAGTCGAAATCCCTCGATAAACTGTGTATGAAG AACAGGAACTACAAGGACCTGGGCAATTGCCATCCAATTGGCATGGTGGTGGGGACACCTG CCTGCGACTTACACCTCACCGGGACATGGGACACTTTGATCGAGAGGGATAATTCAATTGC GTACTGCTATCCCGGGGCCACTGTGAGTGAGGAGGCGCTGAGGCAAAAGATCATGGAGTCT GGGGGCATAGACAAGATTAGCACCGGCTTCACATATGGAAGCTCCATCAACTCAGCTGGCA CGACGAAAGCTTGCATGCGGAACGGTGGGAACTCCTTTTATTCTGAGCTGAAGTGGTTAGT TAGCAAGAACAAAGGCCAGAACTTCCCCCAGACTACAAACACATATAGAAACACAGACTCA GTGGAGCATTTGATCATTTGGGGGATTCACCATCCATCGTCCACACAGGAAAAGAACGACC TGTATGGCACCCAATCGCTGAGCATCTCAGTCGGGTCCAGTACTTATCAGAATAACTTCGT GCCCGTGGTGGGCGCTCGCCCACAGGTAAACGGGCAAAGCGGGAGAATCGACTTCCATTGG ACTATGGTGCAGCCTGGGGATAATATTACCTTCTCCCACAATGGAGGTCTTATAGCCCCCA ATCGAGTTAGCAAACTGAAAGGCCGAGGACTGGGTATCCAGAGCGGCGCAAGCGTGGATAA TGATTGTGAGTCCAAATGTTTTTGGAAGGGAGGATCAATTAATACCAAATTGCCCTTCCAG AACTTGAGCCCTCGCACTGTTGGCCAGTGTCCAAAGTACGTTAACAAGAAATCATTACTGC TAGCCACCGGCATGCGTAACGTGCCTGAGGTCGCCCAGGGGCGCGGTCTCTTCGGAGCAAT AGCAGGATTCATAGAGAATGGTTGGGAGGGAATGGTGGACGGCTGGTATGGATTCCGCCAT CAGAATGCTCAAGGAACCGGCCAGGCTGCGGACTATAAAAGCACGCAAGCTGCGATAGACC AAATTACGGGAAAGCTGAACCGCCTGATTGAAAAGACCAATACTGAGTTTGAATCTATTGA GTCTGAGTTCTCCGAAATCGAACATCAGATTGGGAATGTTATCAACTGGACTAAAGACAGT ATAACTGACATTTGGACGTACCAGGCGGAGCTTCTAGTGGCCATGGAAAATCAGCACACCA TAGATATGGCAGATTCTGAAATGCTGAACCTCTACGAACGAGTGCGAAAGCAATTGCGTCA GAACGCCGAGGAGGACGGCAAGGGATGTTTCGAGATTTACCACAAATGTGACGACAACTGC ATGGAAAGCATTAGGAATAACACTTACGACCATACACAGTACAGGGAAGAGGCCCTGCTCA ACCGCCTCAATATTAACCCGGTGAAACTATCTTCTGGGTACAAGGATGTTATTCTGTGGTT TAGCTTCGGCGCCTCCTGTTTTGTACTGCTTGCCGTGATTATGGGTTTGGTTTTCTTCTGC CTCAAGAATGGCAATATGAGATGTACAATTTGCATA 745 ATGTACAAGATCGTGGTCATCATTGCGCTCCTGGGTGCCGTGAAAGGGCTTGACAAGATCT GCCTGGGTCACCATGCTGTCGCCAATGGGACAATAGTGAAGACTCTTACCAACGAGAAGGA AGAAGTCACCAACGCAACAGAGACTGTCGAGAGTACCGGCTTAAACAGACTTTGTATGAAA GGGCGCAAGCACAAGGACCTGGGGAACTGTCACCCAATTGGCATGCTGATAGGGTCTCCAG CCTGTGATCTGCACCTAACTGGCACATGGGACACCCTGATTGAGAGAGAAAACGCCATTGC ATACTGTTATCCAGGTGCCACCGTTAATGGGGAGGCATTGAGGCAGAAAATCATGGAGTCC GGAGGAATAGACAAGATATCAACAGGGTTCACATATGAGAGCTCTATCAACTCGGCTGGGA CAACCAGGGCATGTATGCGCAACGGAGGAAATTCGTTCTATGCCGAGCTGAAATGGCTTGT TAGCAAGTCTAAGGGCCAGAATTTTCCTCAGACTACCAATACATACCGCAACACCGACACT GCCGAGCATCTGATTATGTGGGGGATTCACCACCCCTCTAGTACTCAGGAGAAGAACGACT TGTACGGGACACAAAGCCTGTCAATTAGTGTCGGGAGCTCTACATACCGGAATAATTTCGT TCCTGTTGTCGGGGCGAGGCCACAGGTGAACGGCCAGAGTGGGAGGATCGACTTCCACTGG ACTCTCGTCCAACCAGGGGACAACATCACTTTCAGCCACAACGGAGGCCTTATTGCTCCTT CGAGAGTCAGTAAGCTGATTGGCAGGGGTTTGGGCATTCAAAGTGATGCCCCAATTGATAA TAACTGCGAAAGCAAGTGCTTCTGGCGAGGGGGCTCTATTAATACTCGATTGCCTTTTCAG AACCTGAGCCCGAGAACAGTTGGGCAATGTCCCAAGTACGTTAATAAGAGGTCTCTGATGC TGGCGACAGGGATGAGAAATGTCCCTGAGCTGATGCAAGGGCGGGGACTGTTTGGCGCTAT AGCGGGCTTCCTCGAAAACGGATGGGAGGGAATGGTTGATGGATGGTATGGGTTCCGACAC CAGAATGCACAGGGCACCGGGCAAGCTGCTGATTACAAGTCTACTCAAGCCGCCATCGACC AGATCACCGGCAAACTTAACCGCCTGGTCGAGAAAACAAATACAGAATTTGAATCTATTGA ATCCGAGTTCTCTGAGATAGAACACCAAATCGGCAACGTGATTAATTGGACCAAGGATAGT ATCACAGATATCTGGACCTATCAAGCGGAGCTGCTGGTGGCCATGGAGAACCAGCACACAA TCGATATGGCTGACTCAGAGATGCTTAATTTGTATGAGCGGGTTCGCAAGCAGCTCCGACA AAATGCTGAGGAGGATGGAAAGGGATGTTTTGAGATCTATCATGCCTGCGACGACTCATGC ATGGAAAGCATTCGCAATAATACCTATGATCATTCACAGTACAGAGAAGAGGCTCTCCTGA ACAGGCTGAACATAAACCCCGTTACACTTTCTAGCGGGTACAAAGACATTATCTTATGGTT CAGTTTCGGAGCATCTTGCTTCGTACTACTGGCCGTTGTCATGGGCCTGGTGTTCTTCTGT CTAAAGAATGGGAACATGCGCTGCACCATTTGCATT 746 ATGTACAAGATCGTCGTGATTATCGCCTTATTGGGAGCAGTCAAGGGGCTCGATAAGATCT GTTTAGGGCATCATGCGGTTGCAAACGGCACTATCGTTAAGACCTTGACAAATGAACAGGA GGAAGTGACGAATGCCACTGAAACCGTTGAGTCCACTGGGATTAATCGGCTGTGCATGAAA GGACGAAAGCATAAGGACCTTGGAAACTGCCACCCCATTGGCATGCTGATTGGGACCCCTG CTTGCGACCTGCATCTGACTGGAACCTGGGATACCCTTATTGAGCGAGAAAATGCCATCGC CTATTGCTATCCAGGCGCCACAGCAAACGTCGAGGCCCTCAGACAGAAAATCATGGAGTCC GGTGGAATTGACAAAATCTCTACCGGCTTTACCTACGGGTCTAGCATCAATTCCGCAGGGA CTACGAGGGCATGTATGAGAAATGGCGGCAACAGCTTCTATGCCGAGCTTAAATGGCTTGT TTCAAAATCCAAGGGACAGAACTTCCCTCAGACTACAAACACTTATCGGAATACAGATACA GCAGAACACTTGATTATGTGGGGCATTCACCACCCAAGCAGTATCCAGGAGAAAAATGACC TCTACGGCACGCAGTCACTGAGTATATCCGTGGGCTCTTCAACCTACAGGAACAATTTTGT CCCCGTCGTCGGTGCGAGGCCTCAAGTGAACGGGCAATCGGGAAGGATCGACTTCCATTGG ACACTGGTGCAACCTGGAGATAATATCACGTTTAGCCACAACGGAGGCTTGATTGCTCCAT CCAGAGTGAGCAAACTGATCGGCAGGGGCCTAGGGATCCAATCAGACGCACCAATCGATAA CAACTGTGAGTCTAAGTGTTTCTGGAGAGGTGGCAGCATTAACACCCGGTTGCCCTTCCAG AATTTGAGCCCCCGGACTGTCGGTCAGTGCCCAAAGTACGTGAATCGGCGCTCTCTTATGC TGGCCACCGGAATGAGGAACGTCCCCGAGCTCATACAGGGCCGGGGTTTATTCGGGGCAAT TGCTGGGTTCCTGGAGAACGGCTGGGAAGGCATGGTGGATGGCTGGTACGGATTTAGGCAC CAGAACGCACAAGGCACTGGCCAAGCCGCGGACTACAAATCAACTCAAGCTGCCATCGATC AGATAACCGGGAAGTTGAACAGACTGGTAGAAAAAACCAATACCGAGTTCGAGTCAATTGA GTCCGAGTTTAGTGAGATAGAACACCAGATCGGTAACGTGATCAACTGGACAATGGATAGT ATTACTGACATTTGGACCTATCAAGCAGAACTGCTGGTGGCGATGGAGAACCAGCACACTA TCGACATGGCAGACAGCGAAATGCTTAACCTGTACGAACGGGTGCGGAAACAGCTAAGACA AAACGCCGAAGAGGACGGCAAAGGTTGCTTCGAAATCTACCACGCCTGTGACGACTCTTGT ATGGAAAGCATAAGGAACAATACCTACGATCACTCCCAGTACCGAGAGGAGGCGTTACTCA ATAGACTGAACATCAACCCTGTGACCCTGAGCTCTGGATATAAAGACATCATTCTCTGGTT TTCTTTTGGGGCCAGCTGCTTCGTGCTTCTCGCAGTCGTTATGGGACTCGTGTTCTTCTGC TTGAAGAACGGTAATATGAGATGCACAATCTGCATA 747 ATGTATAAGATTGTCGTGATTATTGCCCTGTTAGGGGCCGTGAAAGGACTAGATAAAATTT GCCTGGGCCACCATGCTGTCGCCAATGGCACGATCGTTAAAACTTTAACAAACGAGCAGGA GGAAGTAACGAACGCAACAGAGACAGTTGAGAGTACAGGAATCAATAGACTGTGTATGAAG GGGAGGAAACACAAGGATTTAGGAAATTGCCACCCTATCGGAATGCTCATCGGAACTCCAG CATGTGATCTGCATCTGACAGGCATGTGGGACACACTGATCGAGCGGGAAAATGCGATTGC CTATTGCTATCCCGGGGCTACAGTGAATGTCGAGGCTCTGCGGCAGAAGATCATGGAATCC GGCGGCATCAATAAAATTTCTACTGGGTTCACTTACGGGAGTTCTATTAATAGTGCCGGCA CGACCAGAGCCTGCATGCGGAACGGCGGCAACTCGTTCTATGCAGAGCTGAAATGGCTGGT TTCAAAATCTAAAGGACAGAACTTTCCACAAACAACAAATACTTATAGGAACACCGACACC GCCGAGCATCTGATTATGTGGGGAATCCATCACCCAAGTAGCACACAGGAAAAGAACGACC TTTACGGCACTCAGTCACTGAGCATAAGCGTTGGGTCCTCTACTTACCGCAATAATTTCGT GCCAGTCGTCGGCGCTAGACCACAAGTCAATGGGCAATCAGGGAGAATCGATTTTCACTGG ACCCTTGTGCAGCCTGGTGATAATATCACTTTCAGCCACAACGGGGGCCTGATTGCTCCAA GTAGAGTCTCCAAGCTTATTGGACGGGGACTCGGGATTCAGTCTGATGCTCCCATAGATAA TAATTGTGAGTCGAAGTGCTTTTGGCGAGGAGGGTCCATCAACACGCGGTTGCCCTTCCAG AACCTCTCACCTCGGACCGTGGGGCAGTGCCCCAAATACGTGAACAGGAGGAGTCTGATGC TGGCCACCGGGATGCGCAACGTGCCCGAATTGATCCAGGGGAGAGGCCTTTTCGGCGCTAT AGCGGGGTTTTTAGAAAACGGGTGGGAGGGCATGGTGGACGGCTGGTACGGATTTCGCCAT CAGAATGCCCAGGGTACTGGTCAAGCCGCCGATTACAAATCTACCCAGGCTGCCATCGACC AGATTACAGGAAAGTTGAACCGACTGGTGGAAAAGACCAACACTGAGTTTGAGAGTATTGA AAGTGAATTCTCTGAGATCGAACACCAGATTGGGAACGTTATCAACTGGACGAAAGATTCC ATCACAGACATCTGGACCTACCAAGCCGAACTCCTTGTGGCCATGGAGAATCAACACACGA TCGACATGGCTGACTCAGAAATGCTGAATTTGTACGAAAGAGTGAGAAAACAGCTGAGGCA AAATGCCGAGGAGGATGGCAAAGGCTGTTTCGAGATTTATCACGCCTGCGATGATTCCTGT ATGGAATCAATCAGGAATAATACCTACGACCACTCTCAGTACCGCGAGGAAGCCCTATTGA ACCGACTTAACATAAACCCTGTGACTTTGTCCAGTGGTTACAAGGATATCATTCTTTGGTT TTCGTTCGGAGCTTCCTGCTTCGTACTCCTCGCGGTGGTAATGGGCTTATTCTTTTTTTGC CTAAAGAACGGAAATATGAGGTGTACGATCTGCATC 748 ATGTACAAAATTGTGGTGATTATTGCTCTGCTCGGAGCCGTCAAGGGCCTGGATAAGATCT GTCTGGGCCACCACGCCGTGGCCAACGGAACAATTGTGAAGACACTCACAAACGAGCAGGA AGAAGTGACTAATGCCACCGAGACCGTTGAAAGTACCGGGATAAACCGCCTTTGCATGAAG GGTCGGAAACATAAAGACCTGGGGAACTGCCACCCTATAGGTATGCTTATTGGAACACCCG CTTGTGATCTACACCTTACTGGGATGTGGGACACCCTTATAGAGCGCGAGAACGCCATCGC ATACTGTTATCCTGGTGCCACGGTTAACGTGGAGGCTCTTAGGCAGAAGATCATGGAGTCA GGCGGTATTAATAAGATTTCCACAGGCTTTACTTACGGGAGCTCAATAAACAGCGCCGGGA CCACGAGGGCCTGCATGCGGAACGGCGGGAACTCCTTTTACGCGGAATTGAAATGGCTGGT GTCAAAGTCCAAAGGACAAAACTTCCCTCAAACCACTAATACCTACAGGAATACCGACACT GCAGAACATCTTATCATGTGGGGCATACACCACCCGTCGTCTACACAAGAGAAGAACGATC TTTATGGGACCCAGTCTCTGTCCATCAGCGTGGGGTCATCCACTTACCGAAATAATTTTGT GCCTGTGGTTGGGGCTAGGCCACAGGTGAATGGGCAGTCTGGCCGTATTGATTTCCACTGG ACACTTGTGCAGCCAGGGGATAATATAACATTCAGCCACAATGGGGGCCTAATCGCTCCAT CCCGGGTGTCTAAGTTGATCGGTCGCGGACTTGGAATCCAATCTGACGCTCCAATCGACAA CAATTGTGAGTCTAAATGCTTTTGGCGCGGCGGCTCTATCAACACTAGACTGCCATTCCAA AATCTGTCTCCTCGCACCGTTGGGCAGTGTCCTAAGTATGTAAACAGACGGTCCCTGATGC TTGCGACAGGAATGCGGAATGTACCTGAACTCATCCAGGGAAGAGGGCTGTTCGGAGCTAT TGCCGGCTTTCTGGAGAATGGTTGGGAGGGAATGGTAGACGGCTGGTACGGCTTTCGGCAT CAAAATGCGCAGGGAACAGGCCAGGCAGCAGACTACAAATCAACCCAGGCTGCCATTGACC AGATTACAGGGAAGCTCAATAGACTTGTGGAGAAAACAAACACCGAGTTCGAATCCATCGA GTCCGAGTTCAGTGAGATCGAGCACCAGATTGGGAACGTGATAAACTGGACGAAAGATTCT ATCACCGATATTTGGACATACCAGGCTGAGCTCCTGGTCGCCATGGAGAATCAACATACAA TTGATATGGCGGACAGCGAGATGCTGAACCTATATGAGCGCGTACGAAAGCAATTGAGACA GAACGCCGAGGAGGACGGTAAGGGGTGCTTTGAAATATATCATGCTTGTGACGACTCATGC ATGGAATCAATTAGAAATAATACATATGACCACTCTCAATATAGAGAGGAGGCCCTCTTGA ATCGCTTGAACATCAATCCGGTGACTCTCTCTAGTGGGTACAAAGACATTATACTGTGGTT CAGTTTCGGGGCCAGCTGCTTCGTGCTGCTGGCAGTAGTTATGGGGCTCTTCTTTTTTTGC CTGAAAAATGGCAATATGCGATGTACCATTTGTATC 749 ATGTATAAAATTGTCGTGATTATTGCCTTGCTAGGCGCCGTCAAGGGCCTGGACAAAATCT GCCTGGGACACCACGCTGTGGCGAACGGCACTATCGTTAAGACTCTGACCAATGAGCAGGA AAAGGTCACAAACGCTACAGAAACGGTCGAATCTACAGGCCTGAACAGGCTGTGTATGAAA GGTAGAAAGCACAAAGACCTGGGAAATTGCCACCCAATAGGGATGTTAATCGGCACCCCAG CATGCGATTTGCACCTGACAGGTACATGGGACACCATCATCGAAAGGGAGAATGCCATTGC TTACTGTTATCCCGGAGCCACAGTGAATGAGGAGGCCCTCAGACAAAAAATAATGGAATCC GGCGGAATCGACAAGATAAGTACAGGATTTACCTATGGGAGCTCTATTAATTCCGCCGGCA CTACAAGAGCTTGTATGAGGAACGGTGGAAATTCGTTTTACGCAGAGCTTAAATGGCTAGT GAGCAAGTCCAAAGGACAGAACTTTCCTCAGACAACAAATACTTATCGGAACACCGATACG GCTGAACACTTAATAATGTGGGGGATCCACCATCCGTCGTCAACGCAGGAGAAAAATGATC TGTACGGTACGCAATCACTGTCCATCTCCGTAGGCAGCTCCACCTACAGAAATAATTTTGT TCCAGTTGTCGGTGCTCGGCCACAAGTGAATGGCCAGAGCGGCCGAATCGACTTTCACTGG ACCCTGGTGCAGCCAGGGGATAACATCACCTTCAGCCACAACGGTGGCCTTATCGCCCCCT CTAGGGTGAGTAAGCTGATCGGGCGGGGCCTCGGAATCCAATCTGACGCACCCATTGATAA CAACTGCGAGAGCAAGTGTTTCTGGCGGGGTGGTTCTATCAATACCCGACTCCCGTTTCAG AATCTATCTCCTAGGACCGTCGGCCAGTGCCCAAAATATGTGAACAAGCGCAGCCTTATGC TAGCAACTGGAATGAGGAATGTTCCCGAGCTGATTCAGGGCCGAGGTCTCTTCGGAGCTAT TGCCGGGTTTCTCGAGAACGGATGGGAAGGCATGGTGGACGGGTGGTACGGTTTTCGGCAC CAGAACGCCCAGGGAACCGGACAAGCAGCCGATTACAAGAGCACCCAGGCTGCTATCGATC AGATTACCGGCAAGCTCAATCGCTTGGTGGAGAAAACCAATACTGAATTTGAGTCCATTGA ATCAGAGTTCAGCGAGATCGAGCATCAGATCGGGAACGTCATTAATTGGACAAAGGATAGC ATCACCGATATCTGGACATACCAGGCTGAGCTTCTGGTTGCAATGGAAAATCAGCATACTA TCGACATGGCTGATAGCGAAATGTTGAATTTGTATGAAAGGGTGCGTAAGCAGCTGCGGCA GAACGCCGAGGAGGACGGCAAGGGATGCTTCGAGATCTACCACGCATGTGACGACTCATGC ATGGAGAGCATTCGGAACAACACTTATGATCACTCTCAATATCGTGAAGAGGCACTCCTAA ACAGACTAAATATAAACCCGGTCACCCTCAGCAGCGGCTATAAGGACATCATTCTTTGGTT CTCTTTTGGTGCAAGCTGTTTCGTCCTCCTCGCCGTGGTTATGGGCCTGGTGTTTTTTTGC CTGAAGAATGGCAATATGCGGTGCACCATTTGCATC 750 ATGTATAAGATTGTGGTGATTATTGCGTTGCTGGGGGCTGTGAAAGGCCTGGATAAGATCT GTCTTGGGCATCATGCCGTAGCTAACGGCACAATTGTGAAAACTCTGACAAATGAGCAGGA GGAGGTGACAAACGCAACCGAGACCGTTGAGAGCACAGGGATTAATCGCCTGTGCATGAAG GGGCGCAAACACAAGGACCTGGGGAACTGTCACCCTATCGGAATGCTGATCGGGACCCCAG CCTGTGATTTACACCTAACAGGAATGTGGGACACACTCATTGAAAGAGAGAACGCGATAGC ATACTGCTACCCCGGAGCTACTGTGAATGTGGAAGCACTGCGCCAGAAGATTATGGAATCC GGAGGCATAAATAAGATTTCCACTGGGTTCACCTATGGCTCCTCTATCAACAGTGCAGGAA CGACGAGAGCCTGCATGCGCAATGGGGGAAATAGTTTCTACGCCGAGCTGAAGTGGCTGGT GTCTAAGTCAAAGGGTCAAAACTTTCCCCAAACTACCAATACGTACCGAAATACTGACACG GCAGAACACCTAATAATGTGGGGGATTCACCATCCCAGCAGCACCCAGGAGAAGAATGATT TGTATGGGACTCAGTCTCTGTCGATTTCCGTGGGCAGCAGCACGTACCGAAATAATTTCGT ACCCGTGGTTGGAGCTCGACCTCAGGTGAACGGCCAGTCCGGCAGAATTGATTTTCACTGG ACACTAGTTCAGCCAGGCGATAATATAACATTTTCGCACAACGGAGGTCTGATCGCACCTT CACGCGTGTCCAAGCTTATCGGTCGGGGCCTGGGGATCCAGAGTGATGCTCCCATCGATAA CAATTGCGAGTCTAAATGTTTTTGGCGAGGTGGATCCATCAATACCCGTCTGCCCTTCCAG AACCTGTCTCCACGCACAGTCGGTCAGTGCCCCAAGTATGTGAATAGAAGGTCCCTGATGC TCGCCACAGGAATGAGAAACGTTCCGGAACTAATTCAGGGCCGTGGACTATTCGGGGCCAT AGCAGGGTTCCTGGAGAATGGCTGGGAGGGTATGGTTGACGGTTGGTACGGCTTTCGGCAT CAGAACGCCCAAGGGACCGGGCAGGCCGCCGACTACAAAAGTACCCAGGCTGCAATCGACC AGATCACGGGGAAACTGAACCGACTCGTGGAGAAGACTAACACTGAGTTTGAGTCCATCGA GTCTGAGTTTAGCGAAATCGAGCATCAGATTGGGAACGTTATTAACTGGACAAAGGACAGC ATCACCGATATATGGACCTACCAGGCAGAACTATTAGTGGCAATGGAGAACCAGCACACAA TTGACATGGCGGACAGCGAGATGCTGAATCTTTATGAGCGTGTCCGGAAACAGCTGAGACA GAACGCCGAAGAAGATGGCAAAGGCTGCTTTGAGATATACCATGCGTGCGATGATTCATGC ATGGAGTCTATTCGCAATAATACATACGATCACAGTCAGTACAGAGAGGAAGCTCTACTGA ATCGGCTCAACATCAATCCAGTCACCCTGTCTTCCGGCTACAAGGACATCATTCTGTGGTT CAGCTTTGGAGCCTCCTGTTTTGTACTTCTAGCCGTTGTGATGGGCTTGTTTTTTTTCTGT TTGAAGAACGGGAATATGAGATGTACCATCTGCATC 751 ATGTACAAGATCGTGGTAATTATCGCTCTGCTAGGAGCCGTGAAGGGGCTAGACAAGATAT GTCTCGGGCACCACGCCGTGGTTAACGGAACCATTGTGAAGACATTGACTAACGAACAGGA GGAGGTGACCAATGCGACGGAAACAGTTGAGTCAACAGGATTGAATAGGCTGTGTATGAAG GGGCGTAACCACAAAGACCTGGGCAATTGCCATCCAATCGGAATGCTTATTGGAACTCCCG CTTGCGACTTACACCTGACCGGCACATGGGATACCCTGATAGAAAGAGAAAACGCTATTGC GTATTGCTACCCAGGAGCTACCGTAAACGAAGAGGCCCTTCGGCAGAAAATAATGGAGTCC GGGGGAATTAACAAAATATCTACTGGCTTTACTTATGGATCGTCCATCAACAGCGCTGGAA CTACACGCGCTTGCATGCGTAACGGAGGTAATTCATTTTATGCCGAACTGAAGTGGCTGGT GTCAAAGTCAAAGGGACAGAACTTCCCCCAAACTACAAATACATACAGGAATACCGACACT GCTGAACACCTGATTATGTGGGGTATTCACCACCCCTCAAGCACCCAGGAAAAGAATGACC TGTACGGAACTCAGAGTTTGTCTATCAGCGTGGGAAGTTCAACCTACCAAAATAACTTCGT TCCGGTGGTTGGCGCCAGGCCCCAGGTGAACGGACAGTCGGGGCGCATCGACTTTCATTGG ACTTTAGTCCAGCCTGGCGACAATATCACATTCTCCCACAACGGAGGGCTTATCGCCCCGA GTCGCGTGAGCAAGCTCATTGGTCGGGGGTTGGGAATTCAGAGCGATGCCCCTATTGACAA CAACTGCGAAAGCAAGTGCTTCTGGAGAGGCGGTTCTATTAACACAAGACTCCCATTCCAA AACCTGAGCCCACGGACAGTCGGGCAGTGCCCCAAGTACGTAAATAAAAGGTCACTCATGT TGGCTACCGGGATGCGGAATGTCCCAGAACTGATGCAGGGAAGGGGGCTGTTCGGCGCAAT CGCCGGCTTTATTGAGAATGGCTGGGAGGGAATGGTTGACGGATGGTATGGTTTCAGGCAC CAGAATGCCCAGGGTACCGGTCAGGCAGCCGATTATAAATCCACCCAGGCAGCGATTGACC AGATTACTGGAAAGTTGAACCGGCTTATTGAAAAAACCAACACTGAGTTCGAGAGCATCGA GAGTGAGTTCAGCGAGATCGAACATCAGATCGGTAACGTGATAAACTGGACCAAGGACTCC ATCACTGATATTTGGACCTACCAGGCTGAGTTATTGGTTGCCATGGAGAACCAGCACACCA TCGACATGGCCGATTCTGAAATGCTGAATCTCTATGAGAGAGTTCGGAAACAGCTGAGACA AAATGCAGAGGAGGATGGGAAGGGCTGTTTTGAGATTTACCACGCCTGTGACGACAGTTGT ATGGAGTCTATTAGAAATAATACCTACGATCATTCTCAATATCGAGAAGAGGCCTTGTTAA ATAGGCTGAATATTAACCCAGTCACCCTAAGCAGCGGGTACAAAGATATCATACTGTGGTT CTCGTTTGGAGCCTCTTGCTTTGTGCTATTGGCAGTCGTGATGGGTTTGGTGTTCTTCTGC CTCAAAAACGGGAATATGAGATGTACGATTTGCATC 752 ATGTATAAGATTGTCCTTGTGCTCGCCCTGCTCGGAGCAGTGCACGGCCTCGATAAAATCT GTCTGGGGCACCACGCCGTGCCTAACGGCACCATCGTCAAGACTCTCACAAACGAGAAGGA GGAAGTGACAAACGCTACTGAAACAGTAGAAAGTAAGAGCCTGGACAAACTTTGCATGAAA AACAGGAATTATAAAGACTTGGGTAATTGTCACCCGATTGGCATGGTCGTCGGAACGCCTG CTTGTGACCTCCATCTGACGGGAACCTGGGATACCTTGATCGAGCGGGACAACTCAATTGC ATACTGCTATCCAGGCGCCACCGTTAGTGAGGAGGCTTTGAGACAGAAGATCATGGAGTCT GGAGGGATTGACAAAATTTCCACCGGCTTTACATATGGTAGCTCAATCAACTCGGCTGGGA CTACAAAAGCTTGTATGAGGAACGGTGGAAATAGCTTTTACTCGGAACTAAAATGGTTGGT GTCTAAAAACAAGGGTCAGAACTTTCCTCAGACGACCAACACTTATCGAAATACTGACTCC GTGGAGCACCTGATTATTTGGGGGATCCATCATCCCAGCAGCACACAAGAGAAGAATGACC TGTATGGGACGCAGTCTCTGTCCATTAGCGTCGGCAGTTCAACTTACCAGAATAATTTCGT GCCTGTGGTGGGAGCGCGCCCCCAAGTCAATGGGCAGAGCGGAAGGATTGATTTCCACTGG ACTATGGTCCAGCCCGGCGATAACATTACTTTCAGCCACAACGGAGGGCTCATTGCACCAA ACCGTGTCTCAAAACTGAAGGGCAGGGGGCTTGGTATTCAGAGCGGAGCTAGTGTGGACAA TGACTGCGAATCTAAGTGTTTTTGGAAAGGAGGATCAATTAACACTAAGCTTCCGTTTCAA AACCTGAGTCCACGCACAGTCGGACAGTGCCCTAAATATGTGAACAAAAAGTCGCTTCTGC TAGCTACCGGGATGAGGAACGTGCCAGAGGTCGCCCAGGGCAGAGGTTTGTTCGGCGCGAT CGCCGGTTTCATCGAAAACGGATGGGAGGGAATGGTGGATGGCTGGTACGGATTTCGTCAT CAAAACGCACAGGGAACGGGTCAGGCCGCAGATTATAAATCTACTCAGGCCGCTATAGATC AGATCACAGGCAAGCTGAATAGGTTAATAGAGAAGACGAATACCGAGTTTGAGAGCATCGA AAGCGAGTTCAGTGAAATAGAGCATCAGATTGGCAATGTGATCAATTGGACAAAAGATTCG ATCACTGATATTTGGACATATCAGGCAGAACTTCTTGTGGCAATGGAGAACCAGCATACGA TTGATATGGCCGATTCGGAAATGCTGAATCTTTACGAGAGAGTCAGAAAACAGCTGCGCCA AAATGCTGAGGAAGACGGGAAGGGGTGCTTTGAAATATACCATAAATGTGACGACAACTGC ATGGAGTCGATCCGCAACAACACATATGACCATACCCAGTACCGTGAGGAAGCTCTGTTAA ATAGACTTAACATCAATCCAGTTAAACTGTCCTCTGGGTATAAAGATGTGATTTTGTGGTT CTCTTTCGGCGCTTCATGCTTTGTCCTCCTCGCCGTCATCATGGGACTGGTGTTTTTTTGC CTCAAAAACGGGAATATGCGATGTACGATATGCATC 753 ATGTATAAAATAGTAGTGATCATCGCTCTGTTAGGAGCGGTGAAAGGGCTCGACAAGATTT GTCTGGGCCACCACGCCGTTGCTAACGGCACCATCGTCAAGACCCTCACTAATGAACAGGA GGAGGTCACTAACGCCACTGAGACAGTTGAATCGACCGGGATTAACCGGTTGTGTATGAAA GGCCGGAAGCATAAAGATCTCGGGAATTGCCACCCAATAGGGATGCTTATCGGCACACCAG CATGCGACCTCCATCTCACGGGCATGTGGGACACCCTTATCGAAAGAGAAAATGCCATTGC CTATTGCTATCCGGGCGCAACCGTGAATGTGGAGGCCCTTCGACAAAAAATCATGGAAAGC GGCGGCATTAACAAAATCAGCACGGGATTCACCTACGGGTCTAGTATCAATTCAGCAGGCA CGACCAGAGCTTGTATGCGTAACGGGGGTAATTCTTTCTACGCAGAGCTGAAATGGCTCGT GTCTAAGAGCAAAGGTCAGAATTTTCCCCAGACTACTAATACATATAGGAATACCGACACT GCGGAGCATCTTATAATGTGGGGCATCCACCACCCATCCTCCACACAGGAAAAGAACGACC TGTATGGTACGCAGTCACTGAGTATAAGCGTTGGGTCCAGCACTTATCGAAATAACTTTGT GCCCGTAGTGGGAGCCCGCCCACAGGTTAACGGCCAGAGTGGCAGAATCGACTTCCATTGG ACCCTGGTGCAGCCCGGCGACAACATCACTTTCTCACATAACGGAGGGTTAATAGCTCCAT CCAGGGTATCCAAACTCATTGGTAGGGGGCTGGGCATCCAATCCGACGCCCCCATTGACAA TAATTGTGAGAGCAAATGTTTCTGGAGGGGTGGAAGCATCAATACCAGACTCCCATTCCAG AATTTATCTCCCCGCACAGTAGGGCAGTGCCCCAAATATGTTAACAGAAGATCCCTGATGC TCGCGACAGGAATGCGGAATGTGCCCGAGCTGATCCAGGGCCGCGGGTTGTTTGGCGCCAT AGCTGGTTTTCTCGAGAATGGTTGGGAAGGGATGGTTGACGGCTGGTATGGGTTTCGCCAT CAGAACGCTCAGGGAACAGGACAAGCTGCCGACTACAAGAGCACTCAAGCAGCAATCGATC AAATCACGGGGAAGCTCAACAGGCTTGTTGAAAAGACTAATACTGAGTTCGAAAGCATTGA GTCCGAGTTTTCCGAGATTGAGCATCAGATTGGGAACGTCATCAACTGGACCAAAGACAGT ATCACGGACATATGGACTTATCAAGCCGAACTCCTGGTGGCCATGGAAAACCAGCACACAA TCGATATGGCTGATTCTGAGATGCTTAACCTGTACGAGCGCGTGCGGAAACAACTGCGGCA AAACGCAGAGGAAGACGGAAAAGGATGTTTTGAAATATACCACGCATGTGATGATAGCTGC ATGGAGAGCATTCGTAACAACACTTATGATCATTCTCAGTACCGCGAGGAAGCTCTCCTAA ACAGACTCAACATTAATCCAGTGACCCTGAGCTCTGGATATAAAGACATTATTCTGTGGTT TAGTTTCGGCGCCAGCTGCTTTGTGCTGCTGGCGGTGGTTATGGGACTGTTCTTCTTCTGT TTGAAAAACGGAAATATGAGATGTACTATTTGCATC 754 ATGTATAAGATAGTAGTAATTATTGCTCTCTTGGGGGCGGTGAAAGGGCTGGATAAAATCT GCCTGGGGCATCACGCCGTGGCCAATGGCACCATTGTAAAAACGCTTACAAATGAGCAGGA AGAAGTGACCAACGCCACAGAAACTGTGGAGAGCACTGGCATCAACCGGCTCTGTATGAAG GGTAGAAAGCACAAGGATCTGGGGAATTGCCACCCCATCGGCATGTTAATAGGCACTCCGG CTTGCGATTTGCACCTTACCGGAATGTGGGACACACTAATCGAGAGGGAAAATGCCATTGC GTACTGCTACCCAGGTGCCACCGTGAATGTCGAGGCACTGAGGCAGAAAATCATGGAATCA GGAGGAATAAACAAGATCTCTACCGGCTTTACGTATGGCTCATCCATCAACTCTGCAGGTA CCACTCGAGCTTGCATGCGGAACGGCGGCAATTCCTTCTACGCAGAACTAAAGTGGCTTGT GTCCAAAAGTAAGGGTCAGAATTTCCCCCAAACTACCAATACGTACAGGAACACTGACACG GCAGAACACCTGATCATGTGGGGCATCCATCATCCCTCCTCTACCCAGGAAAAAAATGACC TGTACGGGACACAGAGCCTGTCCATATCTGTAGGCTCAAGTACATATCGTAACAACTTCGT GCCCGTTGTGGGCGCACGTCCACAGGTTAACGGCCAAAGCGGACGCATTGATTTCCATTGG ACCCTAGTCCAGCCCGGAGACAATATAACCTTCTCGCATAATGGAGGACTGATCGCTCCCT CTCGCGTGTCTAAGCTGATCGGTCGGGGATTGGGGATTCAGAGCGACGCTCCTATTGATAA CAACTGCGAATCCAAGTGCTTTTGGAGAGGGGGCAGCATCAATACTAGATTGCCTTTTCAG AACCTTTCTCCCCGCACAGTGGGGCAATGCCCTAAATACGTCAATAGAAGGTCTCTTATGC TTGCCACCGGAATGCGTAATGTACCAGAACTCATACAAGGTAGAGGGTTATTCGGCGCCAT CGCTGGCTTTCTGGAAAATGGCTGGGAGGGGATGGTTGACGGCTGGTATGGTTTCAGACAC CAAAATGCTCAGGGTACAGGTCAGGCCGCCGATTACAAGTCCACACAGGCAGCTATTGATC AGATCACAGGCAAGTTGAACCGCCTCGTGGAAAAGACTAACACAGAGTTTGAGTCTATTGA ATCCGAATTCTCTGAGATTGAACACCAAATTGGAAATGTTATCAACTGGACAAAGGACTCT ATTACCGATATTTGGACCTATCAAGCCGAGTTGTTGGTCGCCATGGAGAATCAACATACTA TTGACATGGCGGACTCTGAAATGCTAAATCTCTACGAGAGAGTAAGAAAGCAGCTTCGACA GAACGCAGAGGAAGACGGAAAGGGATGTTTTGAGATCTATCATGCTTGTGACGATTCGTGC ATGGAATCCATTCGGAATAATACATATGACCATTCTCAGTATAGAGAAGAAGCCCTGCTTA ACCGGCTAAACATCAATCCCGTGACGCTATCATCCGGGTATAAAGATATCATCCTGTGGTT CTCATTCGGGGCTTCGTGTTTTGTGCTCCTGGCGGTCGTGATGGGCCTGTTCTTTTTCTGT CTTAAAAACGGGAACATGCGATGCACCATATGCATC 755 ATGTACAAGGTCGTAGTTATTATCGCGCTGCTAGGTGCAGTTCGGGGGCTCGATAAGATTT GCCTGGGGCACCATGCGGTCGCCAACGGAACTATCGTTAAGACATTAACCAACGAACAGGA GGAGGTGACAAATGCAACCGAGACCGTGGAATCTAAATCCCTGGGTAAGCTGTGCATGAAA GGGAGGAGTTATAACGACCTTGGAAACTGTCACCCAATCGGCATTCTTATCGGGACCCCCG CTTGTGATCTCCATTTAACCGGCACCTGGGATACACTCATTGAGCGCGAAAATGCTGTTGC CTACTGTTACCCAGGAGCTACAGTAAACGAGGAAGCTCTTAGACAGAAGATAATGGAGTCC GGAGGGATTTCCAAGATCAGCACTGGCTTCACCTATGGCACATCAATCAACAGCGCAGGGA CGACAAAGGCCTGTATGAGGAACGGCGGCAACTCATTCTACGCCGAGCTGAAATGGCTGGT GTCAAAGAACAAAGGCCAGAACTTCCCACAAACCACGAACACCTACAGGAACACCGATACC GCAGAGCATCTTATAATATGGGGAATCCACCACCCCTCTTCCACCCAGGAGAAAAATGATC TTTATGGCACTCAATCTTTATCTATATCAGTAGGGTCTTCAACTTACCAGAACAATTTCGT GCCTGTGGTGGGAGCGCGGCCGCAAGTGAACGGTCAGAGCGGTCGTATAGACTTTCACTGG ACCCTGCTGCAGCCAGGTGACAACATCACCTTCTCTCACAATGGTGGGCTAATTGCTCCCT CCAGAGTCAGCAAGCTTATAGGGAGAGGCCTCGGGATACAGTCAGAAGCCCCTATCGACAA TGGGTGCGAGTCGAAGTGTTTCTGGAAGGGTGGATCTATTAACACAAAACTTCCTTTTCAG AACTTATCTCCGAGGACTGTGGGCCAATGCCCTAAATACGTTAACAAGCGCAGTTTAATGC TTGCTACGGGTATGAGGAATGTCCCAGAGATCATGCACGGCCGCGGGCTCTTCGGGGCCAT TGCCGGATTTATTGAGAACGGGTGGGAGGGCATGGTAGATGGATGGTACGGGTTCCGCCAC CAAAACGCACAGGGAACGGGACAGGCAGCTGACTACAAATCAACACAAGCGGCTATCGACC AGATAACAGGCAAGCTGAATAGACTGATCGAGAAAACTAATACAGAGTTCGAGAGCATAGA GAGCGAATTTTCCGAGATCGAGCATCAGATCGGTAACATTATAAATTGGACTAAGGATAGC ATTACTGATATTTGGACCTATCAGGCTGAGCTGCTGGTTGCCATGGAAAACCAACATACAA TCGATATGGCCGATTCAGAAATGCTGAATCTATATGAGAGAGTGAGGAAGCAGCTGAGACA GAACGCTGAGGAGGACGGTAAAGGCTGTTTCGAAATTTACCATGCATGCGACGACTCTTGT ATGGAATCTATCCGCAACAACACATACGACCACTCCCAGTACAGGGAGGAAGCCCTGCTGA ATCGACTGAACATTAATCCAGTCAAGCTTTCCTCTGGTTATAAGGACATCATCTTATGGTT CAGCTTCGGGGCTTCGTGTCTCATTCTCTTGGCTGTGGTAATGGGCTTAGTTTTCTTTTGT CTTAAGAACGGCAACATGAGGTGCACAATTTGCATC 756 ATGTATAAAATCGTGGTTATTATTGCACTGCTAGGGGCCGTCAAGGGCTTAGATAAGATTT GCCTGGGCCACCACGCGGTGGCCAATGGGACCATTGTGAAAACTCTGACCAACGAGCAGGA AGAAGTGACTAACGCCACCGAGACTGTGGAATCAACAGGAATCAATCGTCTGTGCATGAAA GGCAGAAAGCATAAGGACCTTGGAAACTGTCATCCTATTGGGATGCTGATCGGCACCCCAG CTTGTGATTTGCACCTCACCGGTATGTGGGATACTCTTATCGAAAGGGAAAACGCTATCGC TTATTGTTACCCAGGAGCGACTGTCAATGTCGAGGCCCTACGCCAGAAAATAATGGAAAGT GGAGGGATTAATAAGATAAGCACTGGTTTCACGTATGGCAGTTCGATCAATAGTGCCGGAA CAACTCGCGCTTGCATGCGTAATGGTGGAAACTCATTTTACGCAGAGCTCAAATGGCTAGT TTCGAAGTCCAAAGGTCAGAACTTTCCACAGACGACCAACACCTATCGCAATACCGACACT GCAGAGCACCTGATCATGTGGGGAATTCATCACCCGTCAAGCACTCAAGAGAAGAACGATC TTTATGGAACCCAGAGTCTCAGTATTTCCGTTGGCTCGAGTACGTACCGCAATAACTTCGT TCCTGTCGTGGGTGCCAGGCCTCAGGTTAACGGGCAGTCCGGGCGCATCGATTTTCACTGG ACTCTCGTTCAGCCCGGGGATAATATCACATTCAGTCACAACGGTGGGCTGATCGCGCCGT CCAGAGTGTCAAAACTGATCGGCAGGGGCCTGGGCATTCAGAGCGACGCACCAATTGATAA CAATTGTGAGAGCAAATGTTTCTGGCGTGGAGGCAGCATCAATACCCGACTCCCGTTTCAG AATCTGAGCCCCAGAACTGTCGGACAATGTCCTAAATATGTGAATCGGCGCTCCCTGATGC TCGCAACTGGCATGCGGAACGTGCCCGAGTTGATTCAAGGACGCGGGCTGTTCGGTGCCAT CGCTGGGTTCCTGGAAAACGGCTGGGAAGGCATGGTAGATGGATGGTACGGGTTCAGGCAC CAGAACGCCCAAGGGACAGGACAGGCCGCCGACTACAAGAGTACTCAAGCTGCTATTGACC AAATTACCGGAAAACTGAATAGGCTGGTGGAAAAGACCAATACAGAGTTCGAGTCTATCGA GAGCGAGTTTAGCGAGATCGAGCATCAGATTGGTAATGTGATTAACTGGACGAAAGATAGT ATCACCGACATCTGGACATATCAAGCAGAACTTCTTGTGGCTATGGAGAATCAACATACTA TTGACATGGCTGATAGCGAGATGTTGAATCTTTACGAGAGAGTGCGCAAACAGCTGCGGCA GAATGCTGAGGAAGATGGCAAAGGTTGTTTCGAGATCTACCATGCCTGCGACGACAGTTGT ATGGAGAGCATTAGGAATAACACTTACGACCACTCACAATATCGAGAAGAGGCTCTACTCA ACAGGCTAAACATCAATCCAGTGACCCTCTCCTCCGGTTATAAGGATATCATTCTCTGGTT CTCCTTCGGAGCTTCCTGTTTTGTCCTTCTGGCAGTGGTGATGGGATTATTTTTTTTCTGC CTTAAGAATGGGAATATGAGATGTACAATCTGTATT 757 ATGTACAAGATCGTAGTGATTATCGCATTACTTGGCGCCGTGAAGGGACTCGATAAGATTT GCTTGGGCCATCATGCTGTGGCCAATGGCACTATAGTGAAGACACTCACCAATGAACAGGA AGAAGTGACCAACGCCACCGAGACCGTGGAGTCTACAGGCATCAACAGGCTCTGTATGAAG GGCCGTAAGCACAAGGATCTTGGCAACTGCCATCCTATCGGAATGCTCATTGGAACACCAG CTTGTGATCTCCACTTAACAGGCATGTGGGACACACTGATTGAGCGGGAGAATGCGATTGC CTACTGTTATCCCGGGGCCACCGTGAACGTTGAGGCTCTCAGACAGAAAATCATGGAGAGC GGCGGGATAAACAAGATAAGCACAGGCTTCACTTACGGTTCTAGCATTAATTCGGCAGGAA CCACACGGGCCTGCATGCGCAACGGCGGCAATTCATTTTACGCCGAACTTAAGTGGCTGGT GTCCAAGAGCAAGGGCCAGAACTTCCCCCAGACCACTAATACTTACCGCAACACCGACACA GCAGAGCACCTTATCATGTGGGGTATACACCATCCTAGCAGTACCCAAGAAAAAAACGATC TGTACGGAACACAAAGCCTTTCAATTTCTGTAGGAAGTTCCACATATAGGAACAACTTTGT CCCGGTGGTGGGCGCTGGCCCTCAGGTTAATGGCCAGTCCGGGAGGATCGATTTCCATTGG ACACTCGTGCAGCCTGGGGACAACATTACTTTCTCTCACAACGGGGGTTTAATCGCCCCCT CAAGGGTCTCTAAGCTCATCGGGCGCGGTCTGGGAATCCAATCCGACGCTCCTATTGACAA CAACTGCGAGTCAAAGTGCTTCTGGAGAGGTGGATCCATCAACACGCGCCTCCCATTTCAG AACTTGTCCCCGCGTACAGTGGGCCAGTGTCCCAAGTATGTGAATCGACGGAGCTTGATGC TGGCCACTGGGATGAGGAACGTGCCTGAACTTATCCAGGGAAGGGGCCTCTTCGGAGCCAT CGCTGGCTTCCTGGAAAACGGCTGGGAGGGGATGGTGGACGGGTGGTACGGCTTTCGACAT CAGAATGCCCAGGGGACTGGACAGGCAGCAGATTATAAGAGTACCCAAGCCGCCATTGACC AGATCACAGGGAAGCTAAACAGGTTGGTCGAAAAGACTAACACAGAATTCGAATCCATCGA GAGCGAGTTTTCCGAGATTGAGCACCAGATCGGTAACGTGATTAACTGGACGAAAGACTCA ATAACCGATATCTGGACATATCAGGCGGAGTTGCTTGTGGCGATGGAGAACCAGCACACTA TTGATATGGCAGACTCTGAGATGCTCAACCTGTATGAGCGGGTTCGGAAGCAGCTGCGACA AAATGCTGAGGAAGACGGAAAGGGGTGTTTCGAAATCTATCACGCCTGTGATGACTCTTGC ATGGAGTCGATTAGGAACAATACCTATGATCACTCTCAATATAGAGAGGAGGCTTTACTAA ATCGGCTCAACATAAATCCAGTGACCCTGTCCAGCGGATATAAAGACATTATTCTATGGTT CTCTTTCGGAGCGAGCTGCTTTGTGCTTCTCGCTGTGGTGATGGGTCTCTTCTTTTTTTGC CTGAAGAATGGTAACATGCGCTGCACTATTTGTATT 758 ATGTACAAGGTGGTAGTGATTATTGCCCTGCTGGGAGCAGTTAGAGGCTTAGATAAAATTT GCCTCGGGCATCATGCTGTTGCTAATGGTACAATTGTCAAGACCTTAACAAATGAGCAGGA GGAGGTAACCAATGCGACCGAGACGGTGGAGTCTAAGTCTTTGGGGAAACTGTGTATGAAG GGAAGATCATATAACGACCTAGGCAATTGCCACCCCATCGGGATTCTGATTGGGACCCCCG CCTGTGATCTGCACCTGACAGGCACATGGGACACCCTGATCGAACGGGAAAACGCGGTGGC CTATTGCTACCCTGGGGCGACAGTCAACGAGGAAGCTTTGAGGCAGAAAATCATGGAGAGC GGGGGCATCTCTAAAATCTCCACCGGGTTCACGTATGGTACCTCCATTAATTCAGCCGGAA CGACCAAGGCATGTATGCGTAATGGAGGCAACTCCTTCTACGCCGAGCTCAAGTGGCTTGT TTCCAAAAATAAGGGGCAGAATTTCCCTCAGACAACGAACACATACCGGAATACTGACACT GCAGAGCACCTAATCATCTGGGGAATTCACCACCCATCCAGTACGCAGGAAAAAAACGACC TCTACGGGACTCAGTCTCTGTCAATTTCTGTGGGCTCCTCAACATACCAAAATAACTTCGT TCCAGTGGTGGGCGCCCGGCCCCAGGTCAATGGACAGAGCGGAAGGATAGACTTCCACTGG ACACTCCTTCAGCCGGGGGACAATATCACGTTCTCTCACAACGGGGGACTGATAGCTCCAT CTAGGGTGAGCAAACTGATTGGACGGGGATTGGGCATACAATCAGAAGCGCCCATAGACAA TGGATGCGAAAGCAAATGCTTTTGGAAGGGAGGTTCAATAAACACAAAACTCCCATTCCAG AATCTGTCTCCTAGAACAGTGGGGCAGTGCCCCAAATATGTTAATAAGAGATCTCTCATGC TTGCTACTGGCATGCGGAACGTCCCCGAAATTATGCATGGGAGGGGCCTCTTCGGGGCGAT TGCCGGCTTCATTGAAAATGGCTGGGAAGGAATGGTCGATGGATGGTATGGCTTTCGACAT CAGAACGCACAGGGCACTGGGCAGGCAGCAGACTACAAAAGTACTCAGGCCGCAATAGACC AGATAACCGGAAAGCTCAATCGCCTCATCGAAAAGACAAACACTGAATTCGAAAGTATTGA ATCCGAATTCTCTGAAATAGAGCACCAGATTGGTAATATCATCAACTGGACCAAGGATAGT ATTACTGATATCTGGACATACCAAGCCGAACTGCTGGTAGCAATGGAGAATCAGCACACGA TTGATATGGCAGATTCTGAAATGCTGAACCTGTATGAGCGAGTGCGCAAGCAGCTGCGCCA AAACGCTGAAGAGGATGGGAAAGGCTGCTTCGAAATCTACCACGCTTGCGACGATTCCTGC ATGGAGAGTATCCGGAATAACACCTACGATCATAGCCAGTACAGGGAGGAAGCCCTTCTGA ACAGACTGAACATTAACCCAGTTAAGCTTAGTAGTGGATACAAAGACATAATCCTCTGGTT CTCCTTTGGCGCTTCATGCTTAATTTTACTTGCCGTCGTAATGGGACTGGTGTTTTTCTGC CTTAAGAACGGCAATATGAGGTGCACGATTTGCATC 759 ATGTACAAGATCGTGGTTATTATTGCCTTGTTGGGCGCCGTGAAGGGTCTCGATAAGATTT GTCTGGGCCATCATGCTGTAGCCAATGGCACCATTGTGAAGACGCTCACTAACGAGCAGGA AGAGGTTACGAACGCAACCGAGACAGTGGAGAGCACTGGGATAAACAGACTGTGCATGAAA GGACGTAAACACAAGGACCTTGGTAATTGCCACCCTATCGGGATGCTGATTGGGACACCCG CATGCGACTTGCATTTGACCGGAATGTGGGATACATTGATTGAGCGCGAGAACGCAATTGC CTACTGTTACCCAGGAGCCACCGTCAATGTTGAGGCCCTGCGGCAGAAGATCATGGAGAGC GGCGGCATTAACAAGATATCTACAGGCTTTACATATGGATCATCCATAAATTCAGCAGGAA CTACGCGCGCATGCATGCGCAACGGCGGCAACAGCTTTTACGCTGAGCTTAAGTGGCTCGT CAGTAAGTCAAAGGGCCAGAATTTCCCCCAAACCACCAATACATACAGAAACACCGACACG GCAGAGCACCTGATCATGTGGGGAATCCATCACCCATCTTCCACGCAAGAGAAGAATGACC TATACGGGACTCAGAGCCTCTCCATATCCGTCGGGTCCTCCACCTACAGGAACAACTTTGT ACCTGTTGTAGGGGCTCGCCCCCAGGTGAATGGCCAGAGCGGACGGATCGACTTTCATTGG ACACTTGTTCAGCCCGGCGACAACATTACTTTCTCCCACAACGGAGGTCTGATCGCCCCCA GCAGGGTAAGTAAACTGATTGGCCGCGGCTTAGGAATACAGAGCGACGCCCCAATCGATAA CAATTGTGAATCTAAGTGCTTTTGGAGGGGGGGCAGTATAAACACCCGGCTACCCTTTCAG AATCTGAGTCCACGCACCGTGGGGCAGTGTCCAAAGTATGTGAACCGGAGAAGTTTAATGC TGGCAACCGGCATGAGAAATGTCCCTGAGCTAATTCAGGGTCGCGGGCTTTTCGGCGCAAT CGCAGGCTTTCTCGAAAACGGTTGGGAGGGCATGGTGGACGGGTGGTACGGGTTCCGGCAC CAAAACGCCCAGGGAACTGGGCAGGCCGCCGATTACAAAAGCACTCAGGCAGCTATAGACC AGATCACAGGCAAACTGAATCGGCTGGTGGAAAAGACAAATACAGAGTTCGAGAGCATTGA GAGCGAGTTTAGCGAGATCGAACATCAGATCGGGAACGTTATTAACTGGACCAAGGATAGC ATCACTGATATTTGGACCTACCAGGCTGAACTGTTGGTCGCCATGGAGAACCAGCACACAA TCGACATGGCAGACTCGGAGATGCTTAACCTCTATGAGCGGGTGAGAAAGCAGCTCCGACA GAACGCCGAAGAGGACGGGAAGGGGTGCTTCGAAATTTATCATGCATGTGACGATAGTTGT ATGGAGTCAATCCGCAATAATACTTATGATCATAGCCAGTATCGTGAGGAGGCCCTGCTCA ATCGTCTGAATATAAATCCCGTGACCCTGAGTTCGGGCTACAAAGACATAATACTCTGGTT TTCGTTTGGCGCGAGTTGCTTCGTGCTGTTAGCTGTTGTAATGGGATTGTTCTTTTTCTGC CTAAAAAACGGCAACATGAGGTGTACTATTTGCATC 760 ATGTACAAGATTGTCCTGGTGCTTGCTCTGCTGGGAGCCGTGCACGGCCTCGATAAAATCT GCTTAGGCCACCACGCTGTCCCTAATGGCACCATTGTTAAGACCTTGACAAACGAAAAGGA AGAGGTGACCAACGCCACTGAGACTGTGGAATCCAAGTCACTCGACAAATTATGTATGAAG AACAGGAACTATAAAGATCTTGGTAACTGCCATCCAATTGGCATGGTGGTAGGAACTCCTG CTTGCGATCTACACCTGACGGGCACATGGGACACCCTGATTGAGAGGGACAACTCTATTGC ATACTGCTATCCAGGTGCGACCGTTTCCGAAGAAGCACTCCGGCAGAAGATTATGGAGTCC GGCGGCATCGATAAAATCTCCACCGGCTTCACATACGGAAGTAGCATCAACTCTGCTGGGA CGACCAAAGCGTGTATGAGGAACGGGGGGAATAGTTTCTACTCAGAACTCAAGTGGCTGGT CAGTAAGAACAAGGGGCAGAACTTCCCTCAAACGACCAACACATACCGAAATACAGATTCT GTGGAGCACTTAATCATCTGGGGGATTCATCATCCATCCAGCACGCAGGAGAAAAACGATC TCTATGGTACACAGTCTCTCAGCATCAGTGTGGGAAGCAGTACGTATCAGAACAATTTTGT CCCCGTCGTTGGCGCCCGGCCACAAGTGAACGGACAAAGTGGTCGTATTGATTTTCATTGG ACCATGGTCCAACCTGGTGATAATATAACATTTTCACACAATGGAGGACTGATAGCTCCTA ACAGAGTATCCAAGCTGAAGGGAAGGGGGTTGGGGATTCAGTCCGGAGCATCAGTGGACAA TGATTGCGAGAGCAAGTGCTTCTGGAAGGGAGGTTCCATCAACACGAAGCTGCCTTTCCAG AATCTGAGCCCACGAACAGTGGGACAGTGCCCGAAGTATGTGAATAAGAAGAGCCTTCTGC TTGCGACTGGCATGAGGAATGTTCCTGAAGTTGCGCAGGGAAGGGGGCTATTCGGGGCAAT CGCCGGATTCATCGAGAACGGCTGGGAGGGCATGGTGGACGGGTGGTACGGGTTCAGGCAC CAGAACGCCCAGGGTACAGGGCAGGCCGCTGATTACAAGTCAACACAGGCGGCGATAGACC AGATCACCGGCAAACTGAATAGGCTAATAGAGAAGACTAACACTGAATTTGAATCTATTGA GAGCGAGTTCTCGGAAATTGAACACCAGATCGGAAATGTGATCAATTGGACCAAGGATTCC ATTACCGATATCTGGACTTATCAGGCAGAGCTGTTAGTGGCAATGGAAAACCAGCATACCA TAGACATGGCTGATTCTGAGATGTTGAACCTCTACGAGCGGGTACGGAAACAACTGAGACA GAATGCAGAGGAAGACGGCAAGGGCTGTTTCGAAATCTACCACAAGTGCGACGATAATTGT ATGGAAAGTATACGCAACAATACCTATGATCACACACAATATAGGGAAGAGGCTCTTCTGA ACCGACTGAACATCAATCCCGTGAAACTTAGCTCAGGATACAAGGACGTGATCCTTTGGTT TTCTTTCGGGGCTAGTTGCTTCGTGCTGCTTGCGGTTATCATGGGGCTTGTTTTCTTTTGT CTAAAGAATGGGAATATGAGATGCACAATCTGCATC 761 ATGTACAAAATCGTGGTGATCATCGCCCTCCTGGGAGCTGTGAAGGGCCTTGACAAAATCT GCCTCGGCCACCACGCCGTCGCCAATGGAACCATCGTGAAGACTCTGACCAATGAGCAGGA GGAAGTTACCAATGCAACTGAGACCGTGGAAAGTACCGGGATAAATCGCCTCTGCATGAAG GGAAGGAAACATAAAGACCTGGGGAACTGTCATCCGATTGGGATGCTGATTGGGACCCCTG CCTGTGATTTGCACCTTACCGGCACATGGGACACACTGATCGAGCGAGAAAATGCTATCGC ATATTGTTATCCCGGGGCAACCGCAAACGTAGAGGCCCTACGGCAGAAAATTATGGAGTCC GGTGGCATAGACAAAATAAGCACAGGATTTACCTACGGCTCGAGCATCAACTCTGCTGGCA CCACCAGAGCTTGCATGAGGAATGGCGGGAACTCCTTTTACGCTGAGTTGAAGTGGCTGGT GAGCAAGAGTAAAGGGCAGAACTTTCCTCAGACGACTAATACATATAGAAACACCGACACA GCAGAGCACCTCATAATGTGGGGAATCCATCACCCATCTTCAATTCAGGAGAAGAATGACC TTTATGGTACTCAGAGCCTCAGTATTTCCGTGGGATCTTCTACGTACAGAAACAACTTTGT GCCAGTTGTCGGCGCAAGACCTCAGGTCAACGGGCAGTCAGGGAGAATTGACTTTCATTGG ACACTGGTGCAACCTGGGGATAATATCACTTTTAGCCATAATGGAGGACTGATTGCTCCCA GTAGAGTCTCTAAACTGATTGGGAGGGGACTCGGTATCCAGTCGGATGCTCCTATCGATAA TAACTGTGAGAGCAAGTGTTTTTGGCGAGGGGGATCTATCAATACACGGTTGCCATTTCAG AATCTATCGCCCCGCACGGTTGGTCAGTGCCCCAAGTACGTTAATCGTCGGTCGCTGATGC TGGCTACGGGAATGAGGAATGTTCCAGAACTGATTCAAGGACGCGGTTTGTTCGGCGCCAT CGCAGGTTTCCTTGAAAACGGCTGGGAAGGTATGGTTGACGGTTGGTACGGATTCCGACAT CAGAACGCCCAGGGTACGGGACAGGCGGCTGACTACAAAAGCACCCAGGCAGCAATTGATC AGATCACGGGGAAGCTCAATAGACTGGTGGAAAAGACCAACACGGAATTTGAATCAATTGA GTCCGAATTTTCCGAGATTGAACATCAGATCGGCAATGTCATTAATTGGACAATGGATAGC ATCACTGACATATGGACTTATCAGGCCGAGCTGCTGGTTGCAATGGAGAATCAGCACACTA TCGACATGGCTGATTCCGAGATGCTGAACCTTTACGAGAGAGTGCGCAAGCAGCTCCGGCA GAACGCCGAAGAAGATGGAAAGGGGTGCTTTGAGATTTATCACGCGTGCGACGACAGTTGC ATGGAATCCATCCGGAACAATACTTATGATCATTCTCAGTACCGCGAGGAAGCACTGCTCA ACAGACTGAATATTAACCCAGTGACCCTAAGCTCAGGGTACAAGGACATCATTCTGTGGTT CTCTTTCGGCGCGTCATGCTTCGTGCTGCTGGCAGTTGTGATGGGACTCGTGTTCTTTTGC CTCAAAAATGGAAACATGAGATGTACCATTTGTATC 762 ATGTATAAAGTCGTAGTGATCATCGCACTGTTAGGAGCTGTAAAGGGACTGGACAAGATCT GCTTAGGACACCACGCAGTGGCAAACGGGACCATAGTCAAGACATTGACTAATGAACAAGA GGAAGTCACCAACGCGACTGAAACAGTCGAATCTACAGGAATCAACAGACTTTGTATGAAA GGACGGAAACATAAAGATCTGGGCAACTGTCACCCCATAGGAATGCTGATTGGTACACCAG CTTGTGACTTGCATCTGACCGGCACATGGGACACGCTGATCGAGAGAGAAAATGCCATTGC CTACTGTTACCCTGGGGCTACAGTAAACGTCGAGGCGCTGCGTCAGAAGATCATGGAATCT GGGGGCATCGATAAAATCAGCACGGGGTTCACATACGGATCCAGTATTAATTCTGCTGGCA CTACCCGTGCTTGTATGCGGAACGGTGGAAACTCCTTCTATGCAGAGCTCAAATGGCTGGT TTCTAAGAACAAGGGGCAGAATTTTCCCCAGACGACAAATACATATAGAAATACAGACACT GCTGAGCACCTAATCATGTGGGGCATCCACCACCCAAGTAGTATCCAGGAGAAAAACGACC TGTACGGCACACAAAGCCTGTCAATCTCAGTGGGCTCCTCAACTTACCGCAATAATTTTGT GCCAGTTGTGGGCGCCAGGCCCCAGGTTAATGGTCAGTCTGGGCGCATCGATTTTCATTGG ACTCTGGTGCAACCTGGCGACAATATTACATTCTCTCACAACGGAGGACTCATCGCCCCAT CCAGAGTGTCTAAGTTGATAGGACGAGGGTTAGGCATCCAAAGCGATGCCCCCATTGACAA TAACTGCGAATCAAAGTGCTTTTGGCGGGGAGGATCCATTAACACACGGTTGCCTTTCCAG AATCTGTCTCCAAGGACCGTAGGGCAGTGCCCAAAATACGTGAACAGGCGGTCTCTTATGC TGGCCACGGGGATGCGCAACGTGCCAGAGCTCATCCAGGGGCGTGGATTATTTGGAGCTAT TGCCGGATTTCTGGAAAATGGCTGGGAGGGGATGGTTGACGGTTGGTACGGTTTCAGGCAC CAGAACGCACAGGGCACAGGACAGGCCGCCGACTATAAAAGTACCCAGGCAGCGATTGATC AGATAACCGGAAAGCTGAACAGGTTGGTGGAAAAAACCAATACTGAGTTCGAGTCTATCGA GAGCGAATTCTCGGAAATCGAACACCAGATTGGAAATGTAATCAACTGGACTATGGATAGC ATCACCGATATCTGGACCTACCAGGCTGAACTGTTGGTGGCTATGGAGAATCAACACACGA TCGATATGGCTGACAGCGAGATGCTCAACCTGTATGAACGTGTTAGGAAACAGCTAAGGCA AAACGCTGAAGAAGACGGAAAGGGATGTTTTGAAATATATCATGCATGCGATGACTCATGT ATGGAGTCAATCCGGAACAATACATATGACCATTCTCAGTATAGGGAGGAGGCCCTCCTGA ACAGACTGAATATTAATCCCGTTACCCTATCCAGCGGGTATAAGGACATCATCCTCTGGTT CTCTTTTGGTGCCAGTTGTTTCGTTTTGCTTGCTGTTGTGATGGGACTCGTCTTTTTCTGT CTGAAGAACGGGAACATGAGATGCACCATTTGCATC 763 ATGTACAAAATTGTCGTCATCATAGCACTTCTAGGTGCCGTGAAAGGTTTGGATAAGATCT GTCTAGGCCATCATGCTGTCGCAAACGGCACTATCGTGAAAACTTTGACTAACGAACAAGA GGAAGTGACTAACGCTACGGAGACAGTCGAATCGACCGGGATCAACAGACTGTGCATGAAA GGCCGCAAACACAAAGATTTGGGGAACTGCCATCCTATAGGCATGCTGATTGGGACACCAG CTTGCGACCTCCACCTGACGGGAATGTGGGACACCCTCATTGAGCGGGAGAATGCGATCGC GTACTGTTACCCGGGGGCTACCGTCAATGTGGAGGCACTCAGGCAAAAGATCATGGAGTCT GGCGGCATCAATAAGATTTCCACTGGGTTCACCTATGGATCTAGCATTAATTCTGCAGGTA CAACTAGAGCTTGTATGAGAAATGGGGGGAATAGTTTCTACGCCGAACTTAAATGGCTGGT GAGCAAGTCAAAGGGACAAAACTTCCCCCAGACAACGAATACTTACAGGAATACGGATACC GCAGAGCACTTGATCATGTGGGGGATTCATCATCCATCAAGCACACAGGAAAAAAACGATT TGTATGGGACTCAGTCACTGTCTATTAGCGTGGGATCTAGTACTTACAGAAACAACTTCGT ACCTGTGGTGGGAGCCCGACCACAGGTGAATGGACAGAGTGGGAGGATTGACTTTCACTGG ACCCTGGTGCAACCTGGTGATAATATTACATTTAGCCACAATGGCGGATTGATCGCACCAT CCCGAGTCAGTAAGCTCATAGGCCGGGGACTTGGCATACAGAGCGACGCTCCTATCGATAA CAATTGCGAGTCCAAATGCTTCTGGCGGGGAGGAAGTATAAACACACGGCTGCCATTTCAG AACCTTTCGCCCCGCACGGTCGGCCAGTGCCCCAAATATGTGAATAGGCGTTCACTCATGC TCGCAACAGGAATGAGAAATGTGCCTGAGCTGATTCAGGGCAGGGGGCTTTTCGGTGCTAT AGCGGGATTTTTAGAGAACGGCTGGGAAGGGATGGTTGATGGGTGGTACGGGTTCCGGCAC CAAAATGCGCAGGGAACAGGACAGGCTGCCGACTACAAATCTACCCAGGCTGCAATTGATC AAATAACTGGCAAACTCAATAGGTTGGTGGAAAAGACGAACACCGAGTTCGAGTCAATCGA ATCTGAATTCAGCGAGATTGAACACCAAATCGGAAATGTGATTAACTGGACCAAGGACTCC ATCACCGACATCTGGACCTATCAGGCCGAACTGCTCGTCGCTATGGAGAACCAGCATACCA TAGATATGGCCGACAGCGAGATGCTCAACCTTTACGAGCGCGTCAGGAAACAGCTTAGGCA GAATGCTGAAGAAGACGGGAAGGGATGTTTTGAGATCTATCACGCTTGCGATGATTCCTGT ATGGAGTCCATAAGGAACAACACCTATGACCATTCACAGTACCGTGAAGAGGCCTTGCTTA ACCGCCTCAACATAAATCCCGTTACTCTCAGCTCAGGTTATAAGGATATCATCCTGTGGTT TAGCTTTGGAGCCTCCTGCTTTGTGCTCCTCGCCGTCGTGATGGGCCTATTCTTTTTTTGT CTGAAAAACGGGAATATGCGATGCACTATATGTATA 764 ATGTATAAGATCGTGGTGATCATTGCACTCCTGGGAGCCGTCAAGGGCCTGGATAAAATAT GCCTGGGGCACCACGCCGTTGCCAACGGAACTATAGTAAAGACCCTGACCAATGAACAGGA AGAAGTGACCAACGCAACCGAAACCGTGGAGAGTACAGGCATAAATCGCCTTTGCATGAAG GGTCGAAAGCACAAAGACCTGGGGAATTGCCACCCCATAGGGATGCTGATCGGCACCCCGG CTTGTGATTTGCACTTGACTGGGATGTGGGATACACTCATTGAGCGCGAAAACGCAATCGC ATATTGCTACCCCGGGGCAACCGTGAACGTCGAGGCCCTGCGGCAGAAAATTATGGAGTCT GGCGGAATAAATAAGATTTCAACCGGTTTTACATACGGAAGTTCTATTAATAGCGCAGGCA CAACAAGGGCGTGTATGAGGAACGGTGGTAATAGTTTCTATGCAGAACTAAAATGGTTGGT GTCTAAATCGAAAGGTCAAAATTTCCCCCAAACTACCAACACCTACCGCAATACTGATACT GCCGAACACTTGATTATGTGGGGTATTCACCACCCATCCTCAACACAGGAAAAGAACGATT TGTACGGGACACAGAGTCTGAGTATTAGTGTAGGCTCTAGCACCTACAGAAATAACTTTGT CCCAGTGGTGGGCGCTCGGCCTCAGGTGAATGGCCAATCTGGAAGAATTGACTTCCATTGG ACACTTGTGCAGCCAGGTGATAACATCACTTTTAGCCATAATGGTGGGCTGATTGCCCCTT CCAGGGTGAGTAAACTTATTGGTCGCGGGCTGGGGATACAATCGGATGCCCCTATCGACAA TAATTGCGAATCCAAGTGTTTTTGGAGGGGCGGGTCAATCAATACCAGGCTACCTTTCCAG AATCTGAGTCCACGTACCGTCGGGCAGTGTCCTAAGTATGTCAATCGACGGTCACTGATGC TCGCTACCGGCATGCGGAATGTCCCAGAGCTGATCCAAGGGCGTGGTCTGTTCGGCGCAAT TGCCGGCTTCCTCGAGAATGGATGGGAGGGCATGGTAGATGGATGGTATGGTTTTAGACAC CAAAACGCCCAAGGAACTGGGCAGGCGGCCGATTATAAATCCACTCAGGCCGCAATTGATC AGATTACTGGCAAGCTAAACCGTTTAGTTGAGAAAACGAACACCGAATTCGAGAGCATAGA GAGTGAATTTAGTGAGATCGAGCATCAAATTGGGAATGTGATTAACTGGACCAAAGACTCA ATAACCGATATCTGGACCTACCAGGCAGAGTTACTGGTAGCTATGGAGAACCAGCATACCA TCGACATGGCCGACTCTGAGATGCTCAATTTGTATGAGAGGGTCAGGAAACAACTGCGGCA GAATGCTGAAGAAGATGGAAAAGGGTGCTTTGAAATATATCACGCATGCGACGATAGTTGC ATGGAGTCCATACGAAACAATACCTACGATCACTCACAGTATAGAGAGGAAGCCCTCTTAA ATAGGCTAAATATAAACCCTGTCACACTGAGCTCTGGGTACAAAGATATTATCTTATGGTT CTCATTTGGGGCTAGTTGTTTCGTGCTCCTGGCGGTCGTGATGGGCCTGTTCTTCTTCTGT CTAAAGAACGGTAATATGAGATGTACTATCTGCATT 765 ATGTATAAAGTGGTGGTTATTATAGCGTTGCTGGGCGCTGTTAAAGGTTTGGACAAGATCT GCTTGGGACATCATGCTGTCGCCAACGGGACAATCGTCAAGACCCTGACAAACGAACAGGA AGAGGTCACAAACGCGACTGAAACCGTGGAGAGCACAGGAATTAATCGGCTCTGTATGAAA GGCCGCAAACACAAAGATCTTGGAAATTGCCACCCAATTGGGATGCTCATTGGCACACCAG CCTGTGATCTACATCTGACCGGCACATGGGACACTCTCATCGAACGCGAGAACGCTATCGC ATATTGTTACCCCGGGGCGACCGTGAATGTTGAGGCCCTGCGCCAGAAGATTATGGAGAGT GGAGGCATCGATAAGATATCGACCGGCTTCACTTACGGAAGCTCCATTAACTCCGCTGGTA CCACCCGGGCCTGCATGAGGAACGGCGGCAATTCCTTTTACGCCGAACTGAAGTGGTTAGT GTCTAAAAATAAGGGGCAGAATTTTCCCCAAACCACAAACACATACCGAAACACCGACACG GCCGAGCATCTGATCATGTGGGGGATTCACCATCCTTCTTCCATCCAGGAAAAGAACGATC TGTACGGAACTCAATCTCTCTCCATCTCCGTTGGTTCCTCCACGTATAGGAACAATTTCGT ACCCGTGGTCGGCGCCCGACCACAAGTAAACGGCCAGTCCGGCCGCATCGACTTCCACTGG ACACTTGTGCAGCCAGGAGACAACATTACATTCTCCCATAATGGCGGGCTGATTGCACCCA GCCGGGTCTCCAAGCTTATCGGCCGCGGCCTGGGGATCCAGTCAGACGCGCCCATCGATAA CAACTGCGAAAGCAAGTGTTTTTGGCGGGGTGGATCTATTAACACCCGTCTGCCTTTCCAG AATCTTAGTCCCCGGACAGTGGGGCAGTGCCCCAAGTATGTGAATCGAAGGTCTCTGATGC TGGCCACAGGCATGAGAAATGTGCCAGAGTTGATTCAGGGCCGGGGTCTCTTTGGAGCCAT TGCCGGTTTTCTTGAAAACGGTTGGGAGGGTATGGTCGACGGTTGGTACGGTTTCCGGCAC CAGAACGCACAGGGCACTGGTCAGGCTGCAGATTATAAATCTACACAAGCCGCTATCGACC AGATCACGGGCAAACTAAATAGACTGGTCGAGAAGACTAACACTGAATTTGAGAGCATTGA GTCGGAGTTTTCCGAGATTGAACACCAGATCGGAAATGTGATTAATTGGACAATGGACTCA ATTACTGACATCTGGACATACCAAGCCGAACTGCTGGTTGCGATGGAGAACCAGCACACCA TCGATATGGCCGATAGCGAAATGCTAAATCTGTATGAGAGGGTAAGGAAGCAGCTGCGCCA GAATGCCGAAGAAGACGGGAAGGGTTGTTTTGAGATCTACCATGCTTGTGACGACAGTTGC ATGGAAAGCATTCGAAACAACACTTATGACCACTCGCAATATCGCGAAGAGGCCCTTTTGA ATCGGCTCAACATAAACCCAGTGACACTTTCTTCCGGTTACAAGGATATTATCCTGTGGTT CTCTTTTGGAGCATCGTGTTTTGTACTGCTCGCTGTCGTTATGGGCTTGGTCTTCTTTTGT CTGAAAAATGGCAATATGCGGTGTACCATCTGCATT 766 ATGTATAAGATTGTGGTGATCATTGCACTGCTGGGGGCTGTGAAGGGACTCGACAAGATTT GCCTGGGCCACCATGCCGTTGCAAACGGGACCATCGTCAAAACATTGACAAACGAGCAGGA AGAGGTGACAAACGCCACTGAAACAGTCGAAAGTACGGGGATTAACCGGCTATGTATGAAG GGGAGGAAACATAAAGATCTAGGCAACTGCCACCCCATAGGCATGCTTATCGGCACCCCGG CCTGCGACCTTCACCTGACCGGAATGTGGGATACCTTGATCGAGAGGGAAAACGCCATCGC TTATTGCTACCCAGGAGCCACGGTGAACGTAGAGGCTCTACGACAAAAGATTATGGAGAGC GGCGGAATAAATAAAATATCCACGGGATTCACCTACGGTTCCTCGATAAATTCAGCGGGCA CCACCAGAGCCTGCATGCGCAACGGCGGCAATTCCTTTTATGCCGAGCTTAAGTGGCTCGT TTCCAAAAGCAAGGGGCAGAACTTTCCTCAGACCACAAACACCTATAGGAATACCGACACC GCGGAGCACCTGATTATGTGGGGGATCCACCATCCCTCAAGTACACAGGAAAAGAACGATC TCTATGGAACCCAGAGCCTGAGTATCAGCGTGGGGTCCAGCACATATCGCAACAACTTTGT CCCAGTGGTCGGAGCCCGCCCACAGGTTAACGGCCAATCCGGTCGCATTGACTTTCACTGG ACCTTGGTGCAACCAGGGGATAATATTACCTTCAGCCACAATGGTGGACTGATTGCCCCAA GTCGTGTTTCCAAGCTGATCGGAAGAGGGTTAGGTATCCAGAGTGACGCCCCAATTGATAA TAACTGCGAGAGCAAATGCTTCTGGCGGGGGGGATCGATTAATACGCGTCTCCCCTTTCAG AACCTCTCCCCACGTACGGTCGGGCAGTGTCCAAAGTATGTGAACAGACGTTCACTGATGC TGGCAACAGGGATGAGAAACGTACCCGAGCTGATCCAGGGGAGAGGGCTGTTCGGTGCCAT TGCCGGATTTCTCGAAAATGGTTGGGAGGGAATGGTGGACGGTTGGTACGGATTCCGGCAC CAGAACGCTCAGGGGACCGGCCAAGCAGCTGATTATAAATCTACCCAGGCCGCCATTGATC AGATCACCGGGAAGTTGAACCGCCTCGTGGAGAAGACTAACACAGAGTTCGAGTCTATCGA ATCAGAGTTCAGCGAGATTGAACACCAGATTGGGAACGTGATTAACTGGACCAAGGACTCC ATCACCGACATTTGGACATATCAAGCCGAGCTGCTGGTAGCCATGGAGAACCAGCACACCA TAGATATGGCAGATAGTGAGATGCTGAACCTCTATGAACGCGTGCGAAAGCAACTGCGACA AAATGCTGAGGAGGATGGGAAGGGATGCTTTGAAATCTACCACGCGTGCGACGATTCTTGT ATGGAAAGTATCCGGAATAATACTTATGATCACTCTCAGTATAGGGAGGAGGCACTACTAA ATCGTCTGAATATCAACCCAGTGACCTTATCCTCCGGATACAAGGACATTATCCTGTGGTT CAGTTTTGGCGCTTCCTGTTTCGTGCTCCTGGCTGTAGTGATGGGCTTATTTTTCTTCTGC CTGAAAAACGGAAATATGCGGTGCACCATTTGCATT 767 ATGTATAAGATAGTCGTAATTATCGCACTCCTCGGGGCTGTTAAGGGCCTGGACAAAATCT GTCTGGGTCACCATGCAGTCGCCAACGGAACAATAGTCAAGACTCTGACCAATGAACAGGA GGAGGTTACGAATGCCACGGAAACCGTGGAAAGTACAGGGATCAACCGCCTGTGTATGAAA GGGAGAAAGCATAAAGACTTGGGTAATTGCCATCCAATCGGGATGCTGATTGGAACACCCG CTTGTGACCTCCATTTGACCGGTATGTGGGACACACTGATCGAAAGAGAGAATGCCATCGC GTATTGTTACCCTGGTGCCACTGTGAACGTGGAGGCACTGCGCCAGAAGATCATGGAATCC GGCGGAATCAATAAGATCTCCACCGGATTTACCTACGGATCCAGTATAAATTCAGCCGGGA CGACAAGAGCATGCATGAGAAACGGCGGCAACAGTTTTTACGCCGAGCTGAAGTGGCTTGT GTCCAAGTCTAAAGGCCAGAACTTTCCTCAGACAACCAACACCTACCGTAACACTGATACA GCAGAGCATCTGATCATGTGGGGCATTCACCATCCATCTTCCACCCAAGAAAAGAATGATC TGTACGGAACACAGAGCCTGTCTATTAGTGTTGGATCGTCAACCTACCGGAATAACTTTGT TCCCGTAGTGGGCGCACGCCCCCAGGTGAATGGGCAGTCAGGTCGAATTGATTTTCACTGG ACCCTCGTGCAGCCTGGCGACAATATTACATTCAGTCATAACGGGGGACTGATCGCCCCAA GCCGCGTTTCTAAGCTGATTGGGAGAGGTTTGGGAATTCAGAGCGACGCACCTATCGATAA CAATTGCGAATCAAAGTGCTTTTGGCGGGGGGGCAGCATAAATACCAGACTGCCCTTTCAG AACCTTAGCCCTAGGACAGTCGGGCAGTGTCCCAAATACGTCAACCGCCGGAGTCTGATGC TCGCTACAGGAATGAGAAATGTTCCAGAGCTAATCCAGGGACGAGGACTCTTCGGAGCCAT CGCTGGATTTCTGGAGAATGGCTGGGAGGGGATGGTTGATGGGTGGTATGGCTTTAGACAT CAGAACGCCCAGGGGACAGGTCAGGCCGCCGATTACAAGTCTACCCAGGCCGCGATTGACC AGATCACTGGCAAATTGAATAGGCTGGTTGAGAAAACTAACACTGAATTTGAGTCAATCGA GAGCGAGTTTTCTGAGATCGAACACCAGATCGGGAACGTGATTAATTGGACTAAAGACTCT ATAACGGACATTTGGACCTATCAAGCCGAGTTATTAGTCGCGATGGAGAACCAGCACACAA TAGATATGGCAGACTCTGAGATGCTGAACCTGTACGAGAGGGTGCGGAAGCAATTAAGGCA GAATGCCGAAGAGGATGGGAAGGGATGCTTCGAAATATACCATGCCTGCGACGACTCGTGC ATGGAGAGCATTAGAAACAATACATACGACCATAGCCAGTATCGCGAGGAAGCACTACTGA ATCGGCTGAATATCAATCCAGTCACACTCTCTTCTGGGTACAAAGATATCATTCTGTGGTT TAGCTTCGGCGCCTCCTGCTTCGTCCTTCTGGCCGTGGTTATGGGGCTGTTTTTTTTCTGT CTTAAGAACGGAAATATGAGGTGTACCATCTGTATT 768 ATGTATAAGATTGTGGTGATCATTGCCCTCCTAGGCGCCGTAAAAGGGTTAGATAAAATCT GCCTGGGACACCACGCCGTGGCCAACGGCACTATAGTCAAGACCCTCACTAACGAGCAGGA AAAAGTGACCAATGCTACGGAAACAGTGGAATCTACAGGCCTGAATCGCCTTTGCATGAAA GGCAGGAAACACAAAGACTTAGGGAATTGTCACCCCATTGGAATGTTAATTGGGACTCCAG CTTGCGATCTGCACCTCACTGGTACATGGGATACAATTATTGAACGGGAGAATGCCATCGC ATACTGCTACCCTGGGGCGACCGTCAATGAGGAAGCTCTGCGGCAGAAGATCATGGAGTCT GGTGGCATTGATAAAATCTCCACCGGGTTCACGTATGGGTCTTCAATTAATAGCGCTGGAA CGACTAGAGCTTGTATGCGCAATGGTGGAAATTCCTTTTACGCTGAGCTTAAATGGCTCGT CTCGAAATCCAAGGGACAGAACTTTCCGCAAACTACAAACACTTATAGAAACACAGACACC GCAGAACACCTCATCATGTGGGGGATTCACCACCCTTCTAGTACCCAAGAAAAGAATGACC TCTATGGCACACAGAGCCTGTCCATCTCGGTCGGCAGCAGCACCTACCGGAACAACTTTGT GCCCGTGGTGGGCGCGCGCCCCCAAGTTAACGGACAGTCCGGTCGGATAGATTTCCACTGG ACACTGGTCCAGCCCGGGGATAACATAACGTTCTCTCACAACGGAGGGCTGATAGCTCCTT CTCGAGTGTCAAAATTGATTGGAAGGGGCTTGGGGATCCAGTCCGATGCCCCAATAGACAA TAACTGCGAGTCTAAATGTTTTTGGAGGGGCGGTTCTATAAATACCCGTCTGCCTTTTCAG AATCTTAGCCCCAGAACAGTGGGACAGTGTCCCAAGTACGTAAATAAAAGAAGTCTGATGC TTGCAACCGGCATGAGGAATGTCCCTGAGCTGATCCAGGGTCGTGGCTTGTTCGGTGCCAT TGCGGGCTTCTTGGAAAATGGTTGGGAGGGAATGGTAGACGGATGGTATGGGTTCCGCCAC CAAAATGCTCAGGGGACGGGCCAAGCTGCCGACTATAAGAGTACGCAAGCCGCTATTGACC AGATCACTGGCAAATTGAACAGACTTGTTGAAAAAACAAATACAGAATTCGAAAGCATCGA ATCAGAATTTAGCGAGATTGAGCACCAAATCGGCAACGTGATCAATTGGACAAAAGACTCC ATAACCGATATTTGGACCTACCAGGCCGAGCTGCTCGTGGCTATGGAGAACCAGCACACCA TCGACATGGCTGATAGCGAGATGCTGAATCTATATGAAAGGGTTCGGAAGCAGTTGCGTCA GAATGCGGAGGAGGATGGGAAGGGTTGCTTTGAAATCTATCACGCCTGCGATGACAGCTGT ATGGAGAGCATACGAAATAATACCTATGACCATTCACAGTACCGCGAGGAGGCCCTGCTCA ATCGGCTGAACATCAATCCGGTGACACTGAGCTCTGGCTACAAGGACATCATTCTGTGGTT CTCATTCGGGGCGAGCTGCTTTGTTTTGTTAGCCGTCGTGATGGGCCTCGTTTTCTTCTGC CTGAAGAATGGGAATATGCGCTGTACAATCTGCATC 769 ATGTACAAGATTGTCGTGATTATCGCTTTGCTCGGCGCCGTGAAGGGACTGGATAAAATCT GTCTGGGGCATCACGCTGTGGCTAATGGAACAATTGTGAAGACCCTCACCAATGAGCAGGA GGAAGTGACAAACGCTACAGAGACAGTCGAGTCCACCGGAATCAACAGGCTGTGCATGAAG GGCCGGAAACATAAGGACCTCGGGAACTGCCACCCTATTGGGATGCTGATAGGCACACCTG CCTGTGACTTACACCTTACCGGGATGTGGGATACACTGATAGAACGGGAGAATGCCATAGC ATACTGCTACCCAGGAGCTACGGTGAATGTGGAAGCTCTCCGCCAGAAAATTATGGAATCA GGCGGGATTAATAAGATTTCTACGGGCTTCACTTATGGAAGTTCAATAAATTCAGCCGGAA CAACCCGGGCTTGTATGAGAAATGGTGGAAATTCTTTCTACGCAGAACTCAAGTGGCTTGT TAGCAAGTCCAAGGGCCAAAACTTCCCTCAGACCACTAATACTTACAGGAATACTGACACC GCCGAACACCTTATCATGTGGGGTATCCACCATCCATCTAGCACCCAGGAGAAAAATGATC TTTACGGTACCCAATCACTGAGCATCAGCGTGGGGAGCTCAACTTATCGCAACAATTTCGT GCCTGTGGTGGGTGCCCGACCACAGGTTAACGGACAAAGTGGACGAATTGACTTTCATTGG ACCCTGGTGCAGCCTGGCGACAACATCACATTCTCGCATAATGGAGGTTTGATCGCTCCCT CCCGTGTGTCTAAGCTGATAGGGAGAGGCCTCGGTATACAGTCCGACGCTCCCATCGATAA TAATTGTGAAAGCAAGTGCTTTTGGCGAGGTGGCAGCATTAACACGCGGTTACCCTTTCAG AACCTCAGCCCACGCACAGTCGGCCAATGCCCTAAGTATGTAAACCGCCGGAGCTTGATGC TGGCAACGGGCATGAGAAACGTCCCCGAGCTAATCCAGGGCAGAGGACTGTTCGGCGCCAT TGCTGGCTTTCTTGAGAACGGATGGGAGGGAATGGTGGACGGCTGGTACGGATTCCGGCAC CAGAACGCCCAGGGCACCGGCCAGGCCGCCGATTATAAGTCCACCCAAGCTGCCATCGACC AGATCACCGGCAAACTGAATCGGCTTGTAGAGAAAACCAACACCGAATTCGAGTCAATCGA GTCCGAATTTAGCGAGATCGAACACCAGATCGGCAATGTGATTAACTGGACAAAGGACAGT ATCACTGATATCTGGACCTACCAAGCAGAATTACTGGTCGCTATGGAAAATCAGCACACCA TTGATATGGCCGACAGCGAGATGCTCAACCTATATGAACGCGTCCGCAAGCAGCTGCGTCA GAACGCAGAGGAAGATGGAAAAGGCTGCTTCGAGATCTACCATGCTTGCGATGACTCTTGT ATGGAGTCCATCCGCAATAACACATACGACCACTCCCAGTACAGGGAGGAGGCGCTTTTGA ACAGACTGAATATAAATCCTGTTACTCTTTCATCGGGGTATAAAGACATCATCCTGTGGTT CTCCTTCGGCGCCTCCTGTTTCGTCCTGCTGGCGGTAGTTATGGGCCTATTTTTTTTTTGT CTGAAGAATGGGAACATGCGCTGTACAATTTGTATC 770 ATGTACAAAATTGTTGTCATCATTGCTCTGCTGGGGGCTGTGAAAGGACTGGACAAAATCT GCTTAGGCCATCACGCTGTAGCCAATGGTACCATTGTGAAGACACTGACCAATGAACAGGA AAAAGTAACAAATGCTACCGAGACGGTCGAGTCCACAGGGCTGAACCGATTGTGCATGAAG GGACGCAAGCACAAGGATCTGGGAAATTGCCACCCGATTGGTATGCTGATTGGGACTCCAG CCTGCGATCTGCATCTGACCGGGACTTGGGATACTATCATAGAACGGGAGAACGCCATCGC CTACTGCTACCCAGGTGCCACTGTAAACGAGGAAGCCTTGCGCCAGAAAATTATGGAGTCA GGTGGGATTGACAAGATTTCCACTGGGTTCACTTATGGGAGCAGTATTAACTCAGCTGGCA CAACCCGTGCTTGTATGCGGAACGGAGGAAACTCATTCTACGCAGAGCTGAAATGGCTGGT TAGCAAAAGCAAGGGCCAGAATTTCCCACAGACAACCAATACATATCGGAACACTGATACC GCAGAGCACCTGATTATGTGGGGCATTCACCACCCATCCTCCACGCAAGAGAAGAATGATC TGTATGGAACTCAGAGCCTGTCAATCTCCGTGGGATCTAGCACATATAGAAATAATTTTGT GCCTGTGGTCGGCGCGCGACCACAGGTTAATGGACAATCAGGACGCATTGATTTCCACTGG ACCTTGGTTCAGCCCGGGGACAATATAACATTCAGCCACAACGGTGGCCTGATCGCCCCCT CGCGGGTGAGTAAGCTGATTGGCAGAGGACTCGGTATTCAGAGCGATGCCCCTATTGATAA TAACTGCGAAAGCAAATGTTTTTGGAGAGGCGGGTCGATCAACACCAGATTACCCTTTCAG AATCTCTCTCCTAGAACCGTTGGTCAGTGCCCGAAATATGTCAACAAGCGTAGTTTGATGC TAGCCACTGGAATGCGCAACGTACCAGAACTCATCCAGGGAAGGGGTTTGTTCGGAGCGAT TGCAGGTTTCCTGGAAAATGGGTGGGAGGGAATGGTGGACGGGTGGTATGGGTTTCGCCAT CAGAACGCACAGGGAACAGGTCAGGCAGCCGACTATAAGTCTACACAAGCCGCCATAGATC AGATCACGGGAAAGCTAAACCGCTTGGTGGAGAAGACAAATACCGAGTTCGAGTCTATAGA GAGTGAGTTTTCCGAGATAGAACATCAAATCGGTAATGTGATCAACTGGACTAAAGACTCG ATAACAGACATCTGGACCTACCAGGCGGAACTGCTCGTCGCCATGGAGAACCAGCACACTA TCGATATGGCTGATTCAGAAATGCTGAACCTGTATGAACGCGTACGGAAACAGCTGCGCCA GAATGCAGAGGAGGATGGGAAAGGCTGTTTTGAAATCTACCACGCCTGCGACGATAGCTGC ATGGAAAGCATCCGCAATAACACATATGACCACTCTCAGTATCGCGAGGAAGCTCTTCTGA ACCGTCTCAACATCAATCCAGTGACGTTGTCATCTGGATACAAAGACATCATATTATGGTT TTCCTTCGGCGCAAGTTGCTTCGTGCTCCTGGCAGTTGTCATGGGCCTGGTCTTCTTCTGT CTCAAGAATGGGAATATGAGATGCACGATCTGTATC 771 ATGTACAAGATTGTTGTGATCATCGCTCTGCTCGGTGCCGTCAAAGGGTTGGATAAGATTT GCCTCGGCCACCATGCAGTAGCCAACGGCACAATTGTGAAAACTCTCACCAACGAGCAGGA AGAGGTCACCAATGCCACCGAAACAGTCGAGTCAACTGGCATTAATCGATTATGTATGAAA GGAAGAAAGCATAAAGACTTGGGAAACTGTCATCCTATCGGGATGCTCATCGGAACACCAG CATGTGACCTCCATTTAACCGGAATGTGGGACACATTAATCGAGCGTGAGAACGCAATTGC CTATTGCTACCCTGGCGCAACAGTTAACGTCGAAGCTTTGAGACAGAAGATTATGGAGTCA GGAGGCATCAATAAAATCTCGACCGGGTTTACCTACGGCTCCTCCATCAACTCGGCTGGCA CAACCAGAGCCTGCATGCGTAACGGAGGCAATAGTTTCTACGCTGAGCTTAAGTGGCTGGT AAGTAAATCAAAAGGTCAAAATTTCCCACAGACTACGAATACTTACAGAAATACAGACACA GCCGAACACCTTATCATGTGGGGGATCCACCACCCTAGCAGTACTCAGGAAAAAAACGATC TGTACGGCACCCAGAGCCTGTCGATCTCTGTGGGAAGTTCAACTTACCGAAATAATTTCGT CCCTGTCGTTGGTGCAAGGCCTCAGGTCAATGGCCAGTCAGGACGCATCGATTTCCATTGG ACTCTGGTGCAACCGGGCGACAACATTACCTTTTCACATAATGGCGGCCTTATCGCCCCCT CCCGAGTGAGTAAGCTGATCGGTCGGGGATTGGGAATCCAGTCTGATGCACCCATTGATAA TAACTGTGAATCTAAATGTTTCTGGAGAGGAGGTTCCATTAATACACGGCTGCCCTTTCAG AACCTGTCCCCTCGAACCGTCGGACAGTGCCCCAAGTACGTGAACAGGAGAAGTCTCATGC TGGCGACAGGGATGAGAAACGTTCCCGAACTGATTCAGGGACGGGGCTTATTCGGGGCTAT TGCAGGCTTTCTGGAAAACGGCTGGGAGGGGATGGTGGACGGCTGGTACGGATTCAGGCAT CAGAACGCACAGGGCACCGGCCAAGCAGCCGACTACAAGAGCACTCAGGCAGCCATCGACC AGATTACAGGAAAACTTAATAGGCTTGTGGAGAAAACCAATACCGAATTCGAGTCAATTGA ATCCGAGTTTAGCGAGATCGAACATCAAATCGGCAACGTGATTAACTGGACAAAGGACTCC ATCACGGACATATGGACTTACCAGGCCGAACTGTTGGTGGCCATGGAAAATCAACATACAA TTGATATGGCAGACAGTGAGATGCTGAACCTGTACGAGAGGGTCAGAAAGCAGCTACGTCA GAACGCTGAAGAGGACGGGAAGGGCTGTTTCGAAATTTATCACGCCTGTGACGACTCCTGC ATGGAATCTATCCGCAATAATACTTATGACCACAGTCAGTATCGCGAAGAGGCCCTCTTAA ACAGATTAAACATCAATCCGGTGACTCTTAGCAGTGGCTACAAGGACATTATTTTATGGTT TTCGTTCGGAGCTAGCTGTTTCGTCCTCCTCGCCGTGGTGATGGGTCTGTTCTTCTTTTGC CTCAAGAATGGAAATATGAGATGTACAATCTGTATA 772 ATGTATAAGATAGTCGTGATCATTGCGCTTCTGGGAGCAGTAAAGGGTCTTGACAAGATTT GTCTGGGCCACCATGCTGTGGCCAACGGGACTATTGTTAAGACTCTGACTAATGAACAGGA AGAAGTTACAAACGCTACTGAGACGGTGGAGAGCACTGGCATAAATAGATTGTGTATGAAA GGGAGGAAACACAAAGACTTGGGTAATTGCCACCCGATTGGGATGCTAATTGGGACTCCCG CTTGTGACCTGCACCTTACTGGCATGTGGGATACCCTAATAGAACGTGAGAACGCCATTGC CTATTGTTACCCAGGCGCTACTGTCAATGTGGAGGCACTTAGGCAGAAGATCATGGAAAGC GGCGGCATCAACAAGATCTCCACCGGATTTACCTATGGTTCAAGTATCAACAGTGCCGGTA CCACCCGCGCTTGTATGCGCAACGGAGGAAACAGTTTTTATGCTGAGCTCAAATGGCTAGT AAGTAAGTCTAAGGGACAAAATTTCCCTCAGACCACCAACACTTATCGTAACACAGACACC GCAGAGCATCTCATTATGTGGGGGATACACCATCCCAGCAGCACACAGGAGAAGAACGATC TGTATGGCACCCAATCGCTCTCCATCTCAGTGGGTTCTTCTACCTATAGAAATAACTTCGT GCCTGTCGTGGGCGCACGGCCACAGGTGAACGGGCAGAGTGGCAGAATCGATTTTCATTGG ACGCTGGTCCAGCCCGGCGATAACATTACCTTCTCACACAATGGGGGATTGATCGCCCCTT CTAGGGTATCAAAATTGATCGGCAGGGGACTTGGGATCCAAAGCGATGCCCCTATTGACAA CAACTGCGAATCGAAATGCTTCTGGCGGGGCGGCAGCATTAATACACGGCTGCCCTTCCAA AATTTATCCCCAAGAACAGTTGGCCAGTGCCCTAAATACGTCAACCGTCGCAGCCTTATGT TAGCCACAGGAATGCGGAACGTCCCGGAGCTTATTCAGGGCAGGGGCCTGTTCGGCGCAAT CGCGGGCTTTCTGGAAAATGGTTGGGAAGGGATGGTTGACGGCTGGTACGGGTTCAGGCAC CAGAATGCCCAGGGAACAGGTCAGGCCGCTGACTATAAGTCAACACAAGCAGCCATCGACC AAATTACCGGCAAGCTGAATAGACTTGTGGAAAAAACGAATACAGAATTCGAGAGTATTGA AAGTGAATTTAGTGAGATTGAACACCAAATTGGCAATGTCATTAACTGGACGAAAGATTCA ATCACCGACATCTGGACCTATCAGGCTGAACTCTTGGTCGCAATGGAAAACCAACATACCA TCGACATGGCTGATTCTGAGATGCTCAACTTATACGAGCGAGTTCGAAAGCAACTGCGGCA GAATGCCGAGGAGGATGGGAAGGGGTGTTTCGAAATTTATCATGCCTGCGACGACAGTTGT ATGGAGAGCATCCGTAATAATACTTATGACCATAGTCAATACAGAGAGGAGGCTCTTCTGA ACAGGCTGAACATCAACCCTGTGACCTTAAGCTCCGGATACAAGGACATTATCTTGTGGTT CAGTTTTGGAGCCTCATGTTTCGTTCTGTTGGCAGTTGTGATGGGCCTCTTCTTCTTCTGC CTGAAAAACGGAAACATGCGTTGCACTATATGCATC 773 ATGTACAAGATTGTGGTCATCATTGCCCTGCTTGGGGCCGTCAAGGGCCTGGACAAAATTT GCTTGGGGCACCATGCCGTGGTTAATGGCACCATCGTCAAAACCCTTACGAACGAACAAGA AGAGGTCACCAACGCCACTGAGACAGTTGAAAGTACAGGCCTCAATCGATTGTGCATGAAA GGTAGGAATCACAAAGATCTGGGGAACTGTCACCCCATAGGGATGCTGATTGGCACACCAG CCTGTGATCTGCATTTGACAGGGACCTGGGATACTCTAATTGAGAGAGAGAACGCTATTGC CTACTGCTACCCCGGCGCCACAGTTAACGAAGAGGCTCTGCGGCAGAAAATAATGGAATCC GGTGGTATTAACAAGATTAGTACAGGGTTTACATACGGATCGTCTATTAATTCAGCTGGTA CAACTCGGGCTTGCATGAGGAACGGTGGCAACTCATTCTATGCAGAACTGAAGTGGTTGGT AAGTAAGTCGAAAGGTCAAAATTTTCCCCAGACAACAAATACATATCGCAATACCGACACC GCGGAACATTTGATCATGTGGGGCATCCACCATCCATCAAGTACACAGGAGAAGAATGACC TTTACGGTACTCAGAGTCTGAGCATTTCAGTTGGATCCAGTACATACCAAAATAACTTCGT TCCTGTCGTCGGAGCCCGCCCGCAGGTAAATGGTCAGTCCGGGCGCATTGACTTTCATTGG ACCCTCGTGCAGCCCGGCGATAACATAACCTTCTCACACAATGGAGGACTGATCGCACCCA GCAGAGTGAGCAAACTTATCGGGAGAGGTCTGGGGATCCAAAGTGACGCCCCCATTGATAA CAACTGTGAGTCCAAATGTTTCTGGCGAGGGGGTTCAATTAACACCCGCTTGCCTTTCCAA AACCTGAGCCCTCGGACGGTGGGCCAGTGTCCAAAGTATGTGAATAAACGGTCTCTGATGT TAGCTACTGGCATGAGAAACGTTCCTGAGTTGATGCAGGGAAGGGGTCTCTTCGGCGCAAT CGCTGGCTTTATTGAGAACGGGTGGGAGGGAATGGTGGACGGCTGGTATGGTTTTAGGCAT CAGAATGCCCAGGGCACCGGACAGGCGGCTGATTATAAATCAACTCAAGCCGCCATCGACC AAATCACCGGGAAACTAAACCGTCTGATCGAAAAAACCAATACTGAGTTCGAGTCTATCGA GAGCGAGTTTAGTGAAATCGAACACCAGATTGGAAACGTGATCAATTGGACAAAAGATAGC ATTACCGATATTTGGACCTACCAGGCCGAATTGCTGGTGGCGATGGAAAATCAGCACACAA TCGACATGGCAGACTCGGAGATGTTGAATCTGTATGAGAGAGTGAGGAAGCAGCTGCGCCA GAATGCCGAAGAGGATGGAAAGGGATGCTTCGAGATCTACCATGCATGTGACGACTCCTGT ATGGAAAGCATCAGAAATAATACATACGATCACTCTCAATATCGAGAGGAGGCGCTTCTTA ATCGTTTAAATATCAATCCCGTCACACTGTCCTCTGGTTATAAGGACATAATTTTGTGGTT CTCGTTCGGTGCCAGTTGTTTCGTCCTGCTAGCGGTCGTGATGGGCCTGGTGTTTTTTTGC CTTAAAAACGGGAACATGCGGTGCACCATCTGCATC 774 ATGTACAAGATTGTCGTCATTATCGCGCTGTTGGGGGCCGTCAAGGGACTGGATAAGATTT GTCTGGGCCATCACGCCGTGGCCAACGGCACAATCGTCAAGACTCTGACCAACGAACAGGA AGAGGTCACCAACGCCACAGAAACCGTGGAGAGTACGGGTATTAACCGCCTCTGCATGAAG GGTCGGAAGCATAAGGACCTCGGTAACTGTCATCCAATCGGCATGTTGATTGGCACACCCG CCTGCGACCTGCACCTGACTGGCATGTGGGACACACTGATTGAAAGGGAAAACGCAATCGC GTACTGTTACCCAGGTGCAACGGTGAACGTTGAAGCACTGAGGCAGAAGATCATGGAGAGC GGGGGCATCAACAAAATTAGCACGGGCTTCACATACGGTAGCAGTATCAACAGCGCTGGCA CCACACGGGCCTGCATGCGGAATGGAGGGAACAGTTTCTACGCTGAACTGAAGTGGTTAGT GAGCAAATCTAAGGGTCAGAATTTCCCCCAAACCACTAATACCTACCGCAACACTGACACC GCCGAGCACTTAATAATGTGGGGCATCCATCATCCTTCAAGCACGCAGGAGAAGAACGACC TGTACGGCACCCAGTCTCTGAGTATCTCGGTGGGTTCGTCCACCTATAGAAACAATTTTGT GCCAGTGGTGGGGGCCAGGCCACAGGTCAATGGACAATCGGGACGTATCGACTTTCATTGG ACCCTCGTGCAGCCTGGTGATAACATTACATTCAGCCATAATGGGGGCCTCATCGCCCCCA GTAGGGTCTCCAAGCTCATTGGGAGAGGACTCGGAATCCAGAGTGATGCACCTATTGACAA CAACTGTGAGAGCAAATGTTTTTGGAGAGGCGGGTCTATTAACACTCGATTGCCTTTCCAA AATCTCTCACCTAGGACCGTCGGTCAGTGTCCTAAGTACGTGAATAGGAGAAGCCTCATGC TCGCGACAGGCATGAGAAACGTGCCCGAACTGATCCAGGGCAGGGGACTCTTCGGGGCTAT CGCAGGATTCTTAGAGAATGGGTGGGAAGGAATGGTGGATGGATGGTATGGCTTTAGGCAT CAGAACGCTCAGGGCACTGGCCAAGCTGCGGACTACAAGAGCACTCAGGCCGCAATAGACC AGATTACCGGCAAGTTGAATCGCCTAGTTGAAAAGACTAATACAGAGTTTGAGAGCATTGA AAGCGAGTTTAGCGAAATTGAACATCAGATCGGCAATGTTATAAACTGGACAAAGGACTCC ATAACTGATATATGGACTTACCAGGCAGAGCTACTAGTCGCCATGGAGAACCAGCATACTA TCGACATGGCCGACTCAGAGATGCTGAACCTATACGAAAGAGTTCGGAAGCAGTTAAGACA AAACGCCGAGGAGGACGGAAAGGGTTGCTTCGAAATCTACCACGCATGTGACGACTCATGC ATGGAATCTATCAGGAATAACACATACGATCATTCACAGTATAGGGAGGAGGCTTTGCTGA ATCGCCTCAATATCAATCCCGTCACTTTATCTAGCGGCTACAAGGACATTATCTTGTGGTT CAGTTTTGGTGCCTCTTGCTTTGTGCTCCTGGCAGTGGTGATGGGACTCTTTTTTTTCTGT TTGAAGAACGGTAATATGCGTTGTACAATTTGCATC 775 ATGTACAAGATTGTGGTGATCATCGCACTGCTGGGTGCTGTGAAAGGCCTGGACAAAATAT GTTTGGGTCACCACGCCGTGGCAAATGGCACCATAGTCAAAACCCTCACCAACGAACAAGA GGAAGTGACGAATGCGACTGAAACAGTGGAGTCGACCGGCATCAACCGTCTGTGTATGAAA GGCAGAAAACATAAGGATCTCGGCAATTGCCATCCCATTGGAATGTTAATAGGGACGCCTG CGTGCGATTTGCATCTGACTGGGATGTGGGATACCCTAATAGAGCGGGAGAACGCCATAGC CTATTGCTACCCAGGAGCTACCGTCAATGTGGAAGCCCTACGGCAGAAAATTATGGAAAGC GGTGGTATCAATAAGATTTCCACCGGATTTACATACGGGTCCTCCATCAATTCAGCCGGGA CGACTCGTGCTTGCATGCGCAACGGAGGTAACTCGTTCTATGCCGAACTCAAATGGCTGGT GAGCAAGTCTAAGGGACAGAATTTTCCACAAACAACCAACACCTACCGTAATACCGATACC GCTGAACACCTTATCATGTGGGGCATTCACCACCCTTCCAGCACACAGGAGAAAAACGACT TGTACGGCACACAGTCCCTCAGTATTTCCGTTGGTAGCTCTACTTACAGAAACAATTTTGT TCCCGTCGTCGGTGCCCGTCCTCAAGTCAACGGACAGTCCGGCAGAATTGACTTTCATTGG ACGTTAGTGCAGCCTGGGGACAACATTACCTTCAGCCACAATGGGGGTCTGATTGCGCCGT CCCGCGTTAGCAAGCTGATAGGCCGAGGGCTGGGCATTCAGAGCGATGCACCCATCGACAA TAATTGCGAATCCAAATGCTTTTGGCGGGGTGGGAGTATTAATACTCGCCTCCCCTTTCAA AATCTCTCACCACGCACTGTTGGGCAGTGTCCCAAATACGTGAATCGGCGTAGCTTAATGC TGGCTACAGGGATGAGGAACGTGCCCGAACTGATTCAAGGCCGTGGTCTTTTTGGAGCCAT TGCCGGCTTTTTAGAGAATGGCTGGGAGGGCATGGTTGACGGTTGGTATGGGTTTAGGCAC CAGAACGCCCAGGGCACTGGACAGGCAGCCGATTATAAGTCCACACAGGCCGCTATTGATC AGATTACTGGAAAATTGAATAGACTCGTGGAGAAAACTAACACCGAGTTCGAGTCTATTGA GTCAGAATTTTCTGAGATTGAGCACCAGATCGGTAATGTTATCAATTGGACAAAGGACAGC ATCACTGACATTTGGACGTACCAGGCCGAGCTGCTGGTGGCAATGGAGAACCAGCACACCA TCGACATGGCGGACTCAGAGATGCTGAACCTATATGAAAGGGTGCGTAAACAGCTTAGGCA AAATGCTGAGGAGGACGGCAAAGGATGTTTCGAGATTTATCATGCCTGCGATGACTCCTGC ATGGAATCAATTCGCAATAATACTTATGACCATTCACAGTATCGCGAAGAAGCGCTTCTGA ATCGGCTAAATATTAACCCCGTAACTCTGTCTTCTGGATACAAGGATATTATCCTGTGGTT TAGTTTTGGAGCTTCATGTTTCGTATTGTTGGCCGTGGTGATGGGGCTGTTCTTTTTCTGT CTTAAGAACGGCAACATGAGGTGTACAATTTGCATT 776 ATGTACAAGATCGTCGTGATCATTGCCCTGCTCGGGGCCGTGAAGGGCCTTGACAAGATTT GTCTAGGCCACCATGCAGTTGCTAACGGAACTATTGTCAAGACATTGACCAACGAACAGGA GGAAGTGACAAATGCCACAGAGACAGTTGAGTCTACTGGGATAAACAGATTGTGTATGAAA GGCAGGAAACACAAAGATCTCGGAAATTGTCATCCTATCGGAATGCTGATAGGAACTCCCG CTTGCGATTTGCATTTGACAGGAATGTGGGACACACTGATCGAACGAGAAAACGCCATCGC GTACTGCTACCCCGGTGCCACTGTGAACGTGGAGGCCCTTCGGCAAAAGATCATGGAATCA GGAGGAATCAATAAGATCTCTACCGGGTTCACTTATGGCAGCTCTATCAACTCCGCCGGTA CTACTAGGGCCTGCATGAGAAATGGGGGAAATAGCTTCTACGCAGAACTGAAGTGGCTGGT GAGCAAGTCGAAGGGGCAGAACTTCCCTCAGACTACGAATACCTATCGCAATACCGATACT GCTGAGCATTTGATTATGTGGGGCATCCATCATCCGTCGTCGACGCAAGAGAAAAATGACC TTTATGGCACACAGTCCTTGTCTATTTCTGTAGGGTCTTCTACCTATCGCAATAACTTTGT GCCTGTTGTCGGCGCCAGGCCACAGGTAAATGGACAGTCTGGCAGAATTGATTTCCACTGG ACGCTCGTACAGCCTGGGGATAATATTACATTCTCACACAACGGCGGACTTATCGCCCCGA GCCGTGTCTCAAAGCTGATTGGAAGGGGACTCGGCATTCAGTCCGATGCGCCCATTGACAA CAATTGCGAGAGCAAGTGTTTTTGGCGCGGTGGATCCATCAATACCCGCCTTCCTTTTCAG AATTTATCACCACGTACCGTCGGCCAGTGTCCCAAATATGTGAATCGAAGATCTCTGATGC TGGCCACAGGCATGCGGAACGTCCCTGAGCTGATCCAGGGAAGGGGGCTTTTCGGAGCGAT TGCCGGGTTTCTGGAAAATGGATGGGAAGGAATGGTGGACGGCTGGTACGGCTTCAGACAT CAGAATGCCCAGGGAACCGGGCAGGCTGCGGATTACAAATCTACCCAAGCTGCTATCGACC AGATCACAGGTAAGCTGAATCGGCTCGTGGAGAAAACTAACACTGAATTTGAGTCCATAGA AAGCGAATTTAGTGAAATCGAACACCAAATCGGAAATGTGATTAACTGGACAAAAGATAGC ATTACCGATATCTGGACCTACCAAGCTGAATTGCTGGTCGCCATGGAGAACCAACACACTA TTGACATGGCAGACTCCGAAATGCTAAATTTGTACGAGCGCGTCCGCAAACAGTTGCGGCA AAACGCAGAAGAAGATGGAAAGGGCTGCTTTGAGATCTACCACGCCTGTGACGATTCCTGC ATGGAATCGATACGAAACAATACTTATGACCATAGCCAGTATCGTGAAGAAGCTCTGCTAA ATCGCCTCAACATTAACCCTGTGACATTGAGCAGTGGGTACAAGGATATTATTCTCTGGTT TTCTTTCGGTGCCTCGTGCTTTGTTCTGCTGGCGGTGGTGATGGGACTCTTCTTCTTCTGC CTCAAAAATGGGAATATGCGGTGTACAATCTGTATC 777 ATGTACAAGATCGTCGTTATCATTGCCCTGCTGGGAGCAGTAAAAGGACTGGACAAAATTT GCTTAGGCCATCACGCGGTGGCAAATGGGACCATCGTAAAGACACTGACCAACGAGCAGGA GGAGGTGACAAACGCTACAGAAACAGTAGAATCGACCGGGATCAACAGGCTCTGTATGAAG GGCCGGAAACATAAGGATCTGGGGAATTGCCATCCTATCGGAATGCTCATTGGTACGCCTG CTTGTGACCTCCACCTCACTGGAATGTGGGACACACTCATCGAGCGCGAGAACGCAATAGC ATATTGTTATCCGGGCGCAACTGTCAACGTTGAGGCACTGAGGCAGAAGATTATGGAGAGT GGGGGCATCAACAAGATATCAACAGGCTTTACATATGGATCGAGCATCAATTCAGCAGGGA CGACCCGGGCGTGCATGAGGAATGGAGGGAATAGCTTTTACGCCGAATTGAAATGGCTCGT GTCTAAGAGCAAAGGCCAAAATTTTCCACAGACAACTAATACCTATCGCAACACCGATACG GCCGAACATCTAATCATGTGGGGAATTCACCACCCAAGTTCGACCCAGGAAAAGAACGATC TCTACGGCACCCAGAGTCTGAGCATCTCGGTGGGATCCTCGACGTACCGGAACAATTTCGT GCCTGTCGTGGGAGCGCGACCGCAGGTTAATGGGCAATCCGGGAGGATCGATTTTCACTGG ACGCTAGTCCAACCCGGGGACAACATCACTTTCAGCCACAACGGTGGACTTATTGCTCCTT CCCGAGTCAGTAAACTCATCGGCCGGGGACTTGGGATTCAAAGCGATGCACCAATAGATAA TAACTGTGAGTCTAAGTGCTTCTGGCGGGGAGGTAGTATTAACACACGACTCCCATTTCAG AACCTGTCCCCAAGGACCGTGGGTCAGTGCCCTAAGTACGTGAACAGACGAAGCCTGATGT TGGCAACCGGAATGAGAAACGTCCCCGAGCTGATCCAGGGGAGGGGACTGTTTGGGGCAAT AGCGGGATTTCTGGAGAACGGATGGGAAGGGATGGTTGACGGATGGTACGGGTTTAGGCAC CAGAACGCCCAAGGGACTGGACAGGCTGCAGATTATAAAAGTACACAAGCGGCCATCGATC AGATCACCGGTAAACTGAATAGACTTGTCGAGAAAACCAATACAGAGTTCGAGTCGATAGA ATCGGAATTCAGCGAGATCGAACACCAGATCGGCAATGTGATCAATTGGACTAAAGACAGC ATCACCGATATCTGGACCTATCAAGCTGAGCTCCTAGTAGCTATGGAGAATCAACACACAA TAGACATGGCTGACTCGGAAATGTTGAACCTGTATGAACGTGTCCGCAAGCAGCTGAGGCA GAACGCCGAGGAGGACGGTAAGGGATGCTTCGAGATCTACCATGCTTGTGACGATTCTTGT ATGGAAAGTATCAGAAACAACACCTACGACCATAGCCAGTACAGGGAAGAGGCCCTGCTGA ATAGACTGAATATCAACCCAGTGACCCTCAGCTCTGGGTATAAAGATATCATTCTGTGGTT CTCATTCGGTGCATCGTGCTTCGTACTGCTGGCCGTTGTCATGGGACTCTTTTTCTTTTGT CTTAAAAATGGCAATATGCGATGCACAATTTGCATT 778 ATGTATAAAATAGTTGTCATCATCGCCCTCCTAGGTGCAGTTAAGGGGCTCGACAAAATTT GTTTAGGCCACCACGCCGTGGCAAACGGCACCATCGTCAAGACCCTTACTAATGAACAAGA GGAGGTGACTAATGCTACAGAGACCGTGGAGTCTACCGGCATAAATCGACTATGTATGAAA GGCCGAAAGCACAAAGATTTGGGGAACTGTCATCCTATCGGAATGCTGATTGGAACCCCAG CCTGCGATCTGCACCTCACCGGCATGTGGGATACCCTGATCGAACGTGAAAATGCTATCGC ATACTGTTACCCTGGAGCCACAGTCAACGTTGAGGCATTGAGGCAAAAGATCATGGAGAGC GGTGGAATCAATAAGATCTCAACAGGGTTTACCTACGGCAGCTCTATAAACTCCGCTGGCA CAACAAGAGCCTGTATGCGCAATGGGGGAAATTCCTTTTATGCCGAACTGAAATGGCTTGT ATCAAAGAGCAAGGGCCAGAACTTCCCCCAAACGACTAATACTTATCGCAACACAGATACA GCTGAGCACCTGATAATGTGGGGTATCCACCATCCATCATCAACGCAAGAAAAGAACGATC TGTACGGGACTCAAAGCCTGTCTATCTCCGTCGGCAGCAGCACATATAGGAATAACTTTGT GCCCGTCGTCGGCGCTAGACCGCAGGTTAACGGACAGAGTGGCCGGATAGACTTCCACTGG ACTCTGGTCCAGCCTGGCGATAACATCACCTTCAGCCACAATGGCGGTTTGATAGCACCCT CTCGTGTGTCTAAGCTGATCGGAAGAGGCCTCGGGATTCAGTCCGACGCCCCGATCGACAA TAACTGCGAGAGTAAATGTTTTTGGAGAGGAGGATCCATTAACACCCGGCTGCCGTTCCAG AATTTGAGCCCTAGGACAGTGGGGCAGTGTCCCAAATATGTCAACCGCCGAAGTCTGATGC TAGCGACTGGCATGAGGAACGTTCCCGAGCTCATCCAGGGACGCGGGCTGTTTGGCGCCAT TGCCGGTTTTCTGGAAAACGGATGGGAAGGTATGGTAGATGGCTGGTATGGATTTCGCCAC CAGAACGCGCAGGGCACTGGGCAGGCGGCGGATTACAAGTCCACACAGGCAGCGATTGATC AGATCACCGGCAAACTGAATCGCCTGGTGGAGAAAACAAATACAGAGTTTGAGTCCATCGA AAGCGAGTTTAGCGAAATTGAGCATCAAATTGGCAACGTCATTAATTGGACAAAAGACAGC ATTACCGATATCTGGACATACCAGGCGGAGCTACTGGTCGCAATGGAGAACCAGCATACCA TCGATATGGCCGACAGTGAAATGCTGAACCTCTATGAGAGAGTGCGAAAGCAGTTAAGACA GAATGCGGAAGAGGATGGGAAAGGTTGTTTTGAGATCTATCACGCCTGTGACGACTCTTGC ATGGAAAGCATTCGAAATAATACCTACGACCATAGTCAGTATCGAGAAGAGGCTCTGTTAA ACCGATTAAATATTAACCCGGTAACTTTGTCGAGTGGGTACAAGGATATTATCCTTTGGTT TTCCTTCGGGGCATCCTGTTTTGTGTTGCTGGCTGTGGTAATGGGACTGTTCTTTTTTTGC TTAAAGAACGGTAATATGAGATGCACAATCTGTATA 779 ATGTATAAAGTAGTTGTGATCATCGCTTTACTGGGCGCAGTCAAAGGTTTGGACAAGATTT GTCTGGGTCACCATGCCGTTGCCAATGGGACCATAGTTAAAACCTTAACAAATGAGCAGGA AGAGGTCACAAACGCTACAGAGACTGTGGAGTCCACTGGGATAAACAGACTGTGTATGAAA GGACGCAAGCACAAGGACCTCGGAAATTGTCACCCAATTGGAATGCTGATTGGCACTCCTG CCTGCGATTTACATCTAACCGGCACATGGGACACCCTGATCGAGCGGGAGAACGCGATCGC CTACTGCTACCCCGGAGCCACCGTCAACGTAGAGGCATTACGGCAGAAGATCATGGAGAGT GGAGGCATAGATAAGATCTCCACCGGATTCACCTATGGTTCTAGCATTAACTCCGCAGGTA CAACAAGAGCTTGCATGCGAAATGGAGGGAATAGCTTTTACGCTGAGCTCAAATGGCTTGT GAGCAAAAACAAGGGACAGAATTTTCCCCAGACCACTAATACTTATAGAAACACTGACACC GCTGAGCACTTAATCATGTGGGGAATCCACCACCCCTCCAGTATCCAAGAAAAGAACGACC TGTATGGAACACAGAGCTTAAGTATCAGCGTGGGGTCATCTACCTACCGGAACAACTTCGT TCCTGTGGTTGGGGCTAGACCACAGGTGAATGGTCAGAGCGGCAGAATCGATTTCCACTGG ACCCTCGTCCAGCCAGGAGACAACATCACCTTCAGCCATAATGGCGGCCTGATTGCCCCTT CTAGGGTTTCCAAATTGATTGGACGCGGCCTCGGGATTCAATCAGACGCTCCCATTGATAA TAATTGTGAGAGCAAATGCTTCTGGAGGGGAGGATCCATTAACACCCGATTGCCATTCCAG AATTTATCCCCACGGACCGTGGGCCAGTGCCCTAAATACGTGAATAGGCGATCCCTGATGT TGGCAACAGGCATGAGAAACGTCCCTGAGCTGATCCAAGGGCGCGGACTATTTGGAGCAAT AGCCGGCTTCTTAGAGAACGGATGGGAAGGAATGGTGGATGGTTGGTACGGTTTCCGACAC CAGAACGCCCAAGGAACTGGACAGGCTGCCGATTACAAATCTACTCAGGCCGCTATAGATC AGATTACAGGAAAACTGAATAGGCTGGTTGAGAAGACGAATACGGAATTTGAATCCATTGA GAGTGAATTCAGTGAGATCGAACACCAGATTGGCAATGTGATTAACTGGACAATGGACTCC ATCACTGATATTTGGACTTACCAGGCCGAGCTGCTTGTAGCGATGGAGAATCAACATACTA TCGACATGGCAGACTCCGAGATGCTGAACCTGTATGAAAGAGTGCGCAAGCAGCTGAGACA GAACGCCGAAGAAGACGGCAAAGGCTGTTTTGAAATTTACCATGCCTGCGACGACTCCTGT ATGGAGTCCATTCGCAACAATACATACGATCACAGCCAGTACAGGGAGGAAGCGTTGCTGA ACAGGTTGAACATAAATCCCGTGACACTTAGCTCTGGTTACAAGGATATTATACTCTGGTT TTCCTTTGGAGCTTCTTGCTTCGTGCTGCTCGCAGTCGTGATGGGTCTGGTTTTTTTTTGC CTCAAGAATGGCAACATGCGTTGCACTATATGTATC 780 ATGTACAAGATCATCGTCATCATCGCTCTCCTCGGTGCGGTGAAGGGTCTGGATAAGATTT GCTTGGGTCACCACGCTGTTGCCAATGGCACGATTGTAAAGACCCTGACTAACGAGCAAGA AGAAGTTACTAATGCCACAGAAACCGTGGAGTCTACCGGCATTAACAGATTATGCATGAAA GGTCGGAAACATAAAGATTTGGGGAATTGCCACCCTATAGGGATGCTCATCGGGACTCCTG CGTGCGACCTCCACCTTACCGGAACCTGGGACACTCTGATTGAGCGCGAAAATGCAATTGC CTATTGTTATCCCGGGGCAACAGTGAACGTCGAGGCCTTGCGGCAGAAGATAATGGAATCC GGCGGAATCGACAAGATTAGCACCGGCTTCACCTACGGCTCCTCTATTAATTCTGCTGGAA CAACTAGGGCTTGCATGAGAAACGGCGGCAACTCATTCTACGCCGAGCTCAAGTGGCTTGT GTCTAAGTCTAAAGGACAAAATTTCCCACAGACCACCAATACGTATCGCAATACAGACACT GCGGAACATCTAATCATGTGGGGCATCCATCACCCGAGTAGTACCCAGGAAAAGAACGACC TCTACGGCACTCAATCACTGTCCATCAGCGTTGGCTCTAGCACATACCGGAACAATTTCGT CCCTGTGGTAGGAGCTAGACCCCAGGTTAACGGACAGTCAGGCCGTATCGACTTTCATTGG ACCTTAGTACAACCAGGGGATAACATTACCTTTTCCCATAACGGGGGACTGATCGCCCCTA GCCGCGTCAGTAAGCTCATCGGACGTGGACTCGGAATCCAGTCAGACGCCCCCATCGATAA CAACTGCGAGTCAAAATGCTTTTGGCGAGGAGGATCTATCAACACTAGGCTGCCCTTTCAA AATCTGTCCCCTCGCACAGTGGGTCAGTGTCCTAAATACGTGAACCGCAGATCACTCATGC TCGCCACCGGAATGAGGAATGTGCCCGAACTCATCCAAGGGAGGGGCCTCTTCGGTGCCAT CGCGGGATTCCTCGAAAATGGATGGGAGGGGATGGTGGATGGATGGTACGGCTTTCGGCAC CAAAACGCTCAGGGCACCGGGCAGGCCGCCGATTATAAATCTACGCAGGCAGCTATAGACC AAATAACCGGCAAATTAAATCGGCTGGTAGAAAAGACCAACACCGAATTCGAGAGCATAGA GAGCGAATTTTCAGAAATAGAGCACCAGATTGGGAACGTAATTAACTGGACAAAGGACTCT ATAACCGATATCTGGACATACCAGGCGGAACTCTTGGTGGCCATGGAGAATCAGCACACCA TTGACATGGCCGATAGTGAGATGCTGAATCTCTACGAGAGGGTGCGAAAACAGCTAAGGCA AAATGCCGAAGAGGACGGCAAGGGTTGCTTTGAGATCTACCACGCCTGCGACGACTCTTGT ATGGAGTCCATTCGAAACAACACCTACGACCATTCTCAATACAGGGAGGAAGCTTTGCTCA ATCGGCTCAACATCAATCCAGTCACGCTGTCTTCCGGTTATAAGGACATCATCCTCTGGTT TAGTTTCGGAGCTTCTTGTTTTGTACTCTTAGCCGTGGTGATGGGCCTGTTCTTCTTCTGC CTAAAAAACGGCAACATGCGGTGCACAATCTGTATT 781 ATGTACAAAATAGTGGTCATCATAGCCCTTCTGGGTGCCGTGAAGGGGCTAGACAAAATCT GTTTGGGACATCACGCAGTAGCGAACGGCACCATCGTCAAAACGCTGACGAACGAGCAAGA AGAGGTTACCAATGCTACAGAGACTGTGGAGTCTACTGGCATCAATAGGCTCTGCATGAAA GGACGGAAACACAAGGACCTGGGCAATTGTCACCCTATCGGCATGTTGATCGGAACTCCCG CCTGTGATCTGCACCTTACAGGGATGTGGGATACGCTGATCGAGCGGGAAAATGCCATAGC TTACTGCTACCCCGGAGCGACCGTTAACGTGGAGGCCTTAAGACAGAAGATCATGGAGTCC GGCGGGATCAATAAGATTTCCACTGGCTTTACGTACGGTTCCAGTATCAACTCCGCAGGGA CGACGCGCGCGTGCATGAGAAACGGCGGCAACAGCTTTTACGCTGAACTCAAGTGGCTGGT TAGCAAGTCAAAGGGCCAGAATTTCCCTCAGACCACTAACACATACAGGAATACTGACACC GCCGAGCACCTCATCATGTGGGGAATTCACCACCCTTCCTCCACCCAGGAAAAGAACGATC TATACGGGACCCAGTCTTTGTCCATATCTGTGGGCAGTTCAACATACCGGAACAACTTTGT GCCTGTGGTGGGTGCTAGGCCACAGGTCAACGGGCAATCCGGTAGGATTGATTTTCACTGG ACTCTGGTCCAGCCCGGGGACAATATAACTTTTTCGCATAATGGCGGGCTGATCGCTCCCT CCCGGGTGTCAAAGCTGATTGGACGGGGCCTTGGTATACAGTCTGACGCGCCCATTGATAA CAACTGCGAGTCTAAGTGTTTTTGGCGGGGAGGCAGCATCAATACTCGCCTCCCTTTTCAA AACCTCTCCCCTAGAACAGTGGGGCAATGCCCAAAATACGTCAATAGGAGGTCCCTCATGC TAGCAACCGGTATGCGCAACGTTCCCGAACTGATCCAGGGCCGAGGGCTGTTCGGAGCTAT CGCAGGGTTTCTCGAAAACGGCTGGGAAGGAATGGTCGATGGCTGGTATGGGTTCAGACAT CAGAATGCCCAGGGCACAGGACAGGCAGCAGATTACAAAAGTACTCAGGCCGCCATCGACC AGATCACCGGCAAACTTAATAGGCTGGTGGAAAAAACCAACACCGAGTTTGAGAGTATAGA GAGCGAGTTTTCAGAGATCGAGCATCAGATTGGGAATGTTATCAACTGGACCAAGGATTCC ATTACTGATATTTGGACTTACCAGGCGGAACTGCTGGTTGCCATGGAGAATCAGCACACGA TCGATATGGCCGACTCCGAAATGTTGAATTTATATGAGCGGGTGAGAAAGCAGCTCAGGCA GAACGCAGAAGAGGACGGAAAGGGGTGCTTCGAGATCTACCATGCTTGTGACGATTCCTGT ATGGAGTCAATTAGAAACAATACCTACGACCACTCCCAGTATAGAGAGGAGGCTCTGCTAA ACCGCCTTAATATCAACCCGGTTACCCTGTCAAGCGGATACAAGGATATTATATTGTGGTT TTCTTTTGGCGCATCTTGCTTCGTGTTACTCGCTGTGGTGATGGGTTTATTCTTCTTTTGT CTGAAGAATGGGAACATGCGGTGTACCATTTGCATA 782 ATGTACAAGGTGGTGGTCATCATTGCCCTGCTGGGGGCAGTCAGGGGCTTAGATAAGATTT GTCTTGGGCATCACGCCGTGGCCAACGGAACGACCGTGAAAACCCTCACAAATGAGCAGGA GGAAGTTACGAATGCCACCGAGACTGTGGAGTCTACTTCTCTGAACAAACTGTGCATGAAA GGCCGGCGTTATAAAGATCTGGGAAATTGTCATCCTATCGGCATGCTGATTGGTACTCCTG TATGTGACCTGCACCTCACGGGCACTTGGGATACACTGATCGAGAGGGAAAATGCCACAGC TTACTGCTACCCCGGAGTCACAATTAACGAGGAGGCACTCAGACAGAAAATCATGGAGAGC GGTGGTATCAGCAAAATGCGCACCGGCTTTACTTATGGCCCAAGCATCAACTCTGCCGGTA CAACACGAAGTTGCATGAGGAACGGCGGCAATAGCTTCTACGCTGAACTCAAGTGGTTAGT CTCCGGTACGAAGGGGCAGAATTTTCCGCAGACTACAAATACATACCGAAATACAGATACA GCTGAGCACCTGATCATCTGGGGCATCCACCACCCTAGTTCAACCCAGGAGAAAAACGATT TGTATGGAACGCAATCTCTCTCCATTTCCGTAGGGTCCTCCACCTATCAAAACAACTTTGT CCCGGTTATTGGGGCTAGACCTCAGGTCAATGGCCAGAGCGGTAGGATTGAGTTTCATTGG ACTCTCGTCAGACCAGGGGACAACATCACGTTTTCCCATAATGGCGGACTCATCGCTCCAG ACAGGGTTTCCAAGCTCATCGGAAAGGGGATTGGGATTCAGTCAGGGGCAGTAATAGATAA GGACTGTGAGTCTAAATGTTTTTGGCGGGGAGGTTCCATAATTACCGAACTGCCATTTCAG AATCTCTCCCCTAGAACAGTGGGGCAGTGTCCCAAATACGTTAAAAAAAGGAGTTTGCTGC TGGCAACAGGCATGCGGAACGTCCCTGAGGTAGTACAGGGGCGGGGATTATTCGGAGCAAT AGCCGGGTTTATCGAAAACGGGTGGGAAGGTATGGTGGATGGATGGTACGGCTTCCGTCAC CAAAATGCTCAGGGGATCGGACAGGCCGCCGACTACAAATCTACTCAGACTGCCATAGATC AGATTACCGGTAAACTCAACAGGCTCATCGAAAAAACAAATACTGAGTTTGAAAGCATTGA GTCTGAGTTTTCTGAGATTGAGCATCAGATTGGCAACGTCATCAACTGGACCAAGGATTCC ATTACAGATATCTGGACGTACCAAGCCGAGCTGCTCGTGGCAATGGAGAACCAGCATACAA TAGACATGGCTGATTCTGAAATGCTGAATCTGTACGAACGTGTGAGAAAGCAACTGAGGCA GAACGCTGAGGAGGACGGCAAGGGCTGTTTCGAGATCTATCATACCTGCGATAACTCATGT ATGGAATCCATCCGGAATAATACTTATGATCACAGTCAGTATCGCGAGGAAGCCCTGCTGA ATAGATTAAATATCAATCCTGTGAAACTGAGTTCTGGGTACAAAGATATCATCCTGTGGTT CAGCTTTGGGGCCAGCTGTTTCGTACTGCTGGCCGTAATCATGGGGCTAGGATTCTTTTGC CTGAAGAACGGCAATATGCGCTGCACGATTTGCATT 783 ATGTACAAAATTGTGGTGATAATTGCCCTTTTAGGCGCCGTGAAGGGCCTCGATAAAATTT GCCTTGGCCATCATGCAGTCGCTAACGGGACTATCGTAAAGACCCTGACCAACGAACAGGA AGAAGTTACCAATGCCACTGAAACTGTGGAGAGTACAGGCATTAACAGGCTGTGCATGAAG GGACGCAAGCACAAGGATTTAGGGAATTGCCATCCGATCGGAATGCTGATCGGGACCCCCG CGTGCGACCTGCACCTGACAGGAATGTGGGACACCCTTATTGAGAGAGAAAATGCTATCGC TTATTGCTACCCTGGTGCCACTGTCAACGTGGAGGCCTTACGTCAGAAGATTATGGAATCC GGAGGCATAAATAAGATTAGTACCGGGTTCACATATGGCTCTTCCATAAACTCTGCGGGCA CCACTAGAGCATGTATGAGGAACGGTGGGAATAGCTTCTATGCTGAGCTCAAGTGGTTGGT CAGCAAGTCCAAAGGTCAGAACTTTCCGCAGACAACTAATACCTACCGAAATACAGACACC GCTGAGCACCTCATTATGTGGGGCATTCACCACCCGAGCTCAACTCAAGAGAAGAATGACT TGTACGGAACACAATCTCTGTCCATCTCTGTGGGCAGCAGTACCTATCGGAATAATTTCGT CCCAGTAGTGGGCGCAGGACCTCAGGTCAATGGTCAGTCCGGTCGCATCGACTTCCATTGG ACCCTGGTGCAACCAGGCGACAACATCACCTTTTCTCACAACGGCGGGCTGATCGCACCCT CGCGTGTGTCTAAGCTAATCGGCCGTGGCCTGGGGATCCAGTCTGATGCACCCATTGACAA TAACTGCGAGTCTAAATGTTTCTGGAGAGGCGGATCCATTAACACGCGGCTGCCATTTCAG AACCTGAGTCCAAGAACGGTAGGCCAGTGTCCGAAGTACGTCAATCGGAGGTCATTGATGC TGGCAACCGGCATGAGAAATGTCCCGGAGCTGATACAGGGAAGGGGACTATTTGGAGCTAT CGCTGGCTTCCTAGAAAATGGATGGGAGGGTATGGTCGATGGATGGTATGGGTTTCGCCAC CAAAACGCACAGGGGACTGGGCAGGCCGCAGATTATAAGAGCACTCAAGCTGCAATCGACC AGATCACTGGCAAACTGAATCGGCTTGTGGAGAAAACCAACACAGAATTCGAGTCAATTGA GTCCGAGTTTAGCGAAATTGAACACCAGATCGGAAATGTTATTAACTGGACTAAGGATTCC ATCACAGATATCTGGACCTACCAGGCAGAGCTATTGGTAGCCATGGAGAACCAACATACAA TCGACATGGCGGATTCAGAAATGCTGAACCTGTATGAACGCGTTAGGAAGCAGCTCAGGCA GAACGCCGAGGAGGATGGGAAAGGTTGCTTCGAGATATATCATGCCTGCGACGACAGCTGT ATGGAGTCCATACGAAATAACACGTATGACCACAGCCAGTACCGAGAAGAGGCTCTTCTTA ATCGGCTCAATATAAACCCAGTGACACTGTCATCCGGATACAAGGACATCATACTATGGTT CAGCTTTGGTGCCTCTTGTTTCGTGCTACTTGCTGTGGTGATGGGCCTTTTTTTTTTCTGC CTCAAGAACGGGAACATGAGGTGTACGATATGCATC 784 ATGTACAAGATAGTCGTGATCATTGCCCTCCTTGGTGCAGTAAAGGGATTAGACAAGATTT GCTTGGGACACCACGCGGTTGCTAACGGAACAATAGTTAAGACACTCACTAATGAGCAAGA GGAAGTCACAAATGCTACCGAAACCGTAGAGTCTACGGGCATCAACAGGCTTTGTATGAAA GGCAGGAAGCACAAGGACCTTGGGAATTGTCACCCTATTGGTATGCTTATTGGCACCCCAG CCTGCGATCTACATCTGACTGGGATGTGGGACACCCTCATCGAACGAGAGAATGCCATAGC CTATTGCTACCCTGGCGCAACTGTGAATGTGGAAGCTTTGAGGCAGAAGATAATGGAATCC GGCGGAATCAACAAGATATCAACAGGCTTTACTTACGGCTCGAGTATCAATTCAGCCGGCA CAACTCGGGCCTGCATGCGGAATGGGGGAAACTCTTTCTACGCAGAACTGAAATGGCTGGT ATCCAAGTCTAAGGGCCAGAATTTCCCGCAGACCACCAACACCTATCGCAACACTGACACA GCAGAACATTTGATAATGTGGGGTATCCACCACCCGTCTAGTACCCAGGAGAAGAACGACT TGTATGGCACGCAGTCATTATCTATCAGCGTGGGCTCCAGCACGTACCGGAACAACTTTGT CCCCGTGGTTGGCGCACGACCACAAGTGAACGGACAATCCGGCCGGATCGATTTTCATTGG ACACTCGTTCAGCCCGGCGACAATATCACCTTTTCTCACAATGGGGGCCTGATCGCGCCAA GCCGGGTTTCCAAGCTGATCGGCAGAGGCCTCGGCATACAGAGCGATGCCCCGATCGATAA CAATTGTGAGTCGAAATGTTTTTGGAGAGGCGGCTCTATTAACACGCGACTGCCCTTTCAG AATCTGAGCCCGCGGACAGTGGGACAATGCCCAAAATACGTAAACAGGAGGAGTCTGATGC TCGCGACTGGCATGAGGAACGTTCCTGAGTTGATCCAGGGCCGGGGCCTATTTGGCGCCAT CGCAGGGTTCCTGGAGAATGGTTGGGAGGGTATGGTAGATGGATGGTACGGGTTCCGCCAC CAGAATGCCCAGGGAACAGGCCAGGCTGCGGACTACAAATCCACTCAGGCCGCCATCGATC AAATTACCGGAAAGCTTAACAGACTCGTCGAGAAAACGAATACAGAGTTTGAGTCAATTGA GTCCGAGTTCAGTGAAATCGAGCACCAAATAGGAAACGTGATCAATTGGACAAAGGACAGT ATCACCGATATCTGGACTTACCAGGCTGAACTGCTCGTAGCTATGGAGAATCAGCACACCA TAGATATGGCAGACTCCGAGATGTTGAATTTATACGAGAGAGTCCGGAAACAGCTGCGCCA GAACGCCGAAGAGGATGGGAAGGGCTGCTTCGAGATATACCACGCCTGTGACGACTCATGC ATGGAGTCTATCCGAAACAATACCTACGATCATTCCCAGTATAGGGAAGAGGCCTTGCTGA ACCGGTTGAATATTAATCCTGTCACATTGTCTAGCGGCTACAAAGACATCATCTTATGGTT TTCGTTTGGTGCTTCATGTTTCGTGCTTCTGGCTGTGGTGATGGGACTCTTTTTCTTTTGC CTTAAGAATGGCAATATGAGATGCACCATTTGTATT 785 ATGTATAAGATCGTGGTGATCATTGCCCTACTGGGTGCCGTGAAAGGGCTGGACAAAATTT GCCTCGGCCACCATGCTGTCGCCAACGGCACCATCGTCAAAACGCTTACGAATGAGAAGGA GGAAGTGACCAATGCTACCGAGACTGTGGAAAGTACAGGCCTCAACAGGCTCTGTATGAAG GGCAGGAAACACAAAGACTTGGGTAACTGCCATCCTATAGGAATGCTCATTGGCAGCCCGG CTTGTGACCTGCACCTTACTGGGACCTGGGATACTCTGATCGAGAGGGAGAATGCCATTGC GTATTGTTATCCAGGAGCCACCGTAAACGGCGAGGCACTAAGGCAAAAGATTATGGAAAGC GGGGGTATTGACAAAATTTCAACAGGGTTCACATATGAGTCTAGCATCAACTCAGCCGGCA CAACGAGAGCATGCATGCGGAACGGGGGCAATTCCTTTTACGCTGAGTTGAAGTGGCTGGT GTCCAAGAGCAAAGGGCAGAATTTCCCACAGACTACCAACACCTATAGAAATACGGATACA GCAGAGCACCTGATTATGTGGGGTATCCACCACCCAAGCTCCACGCAAGAAAAGAATGATC TGTATGGAACTCAAAGCCTCTCTATTAGTGTGGGGTCTAGCACTTACCGGAACAACTTCGT CCCTGTGGTGGGCGCTCGCCCTCAGGTTAATGGCCAGTCCGGAAGAATTGACTTTCATTGG ACTCTCGTCCAGCCAGGGGATAATATAACATTCTCTCACAATGGAGGACTGATTGCACCTT CTCGGGTGAGCAAGCTGATAGGCCGCGGGCTGGGGATCCAGAGCGATGCTCCAATAGATAA TAATTGCGAATCAAAGTGCTTTTGGAGGGGGGGATCTATTAATACGCGGCTTCCATTCCAG AACCTCAGTCCTCGGACTGTTGGACAATGCCCCAAATATGTGAACAAGCGCAGCCTTATGC TCGCTACCGGGATGAGGAATGTCCCTGAATTAATGCAGGGACGCGGCCTATTCGGAGCAAT TGCCGGATTTCTCGAGAACGGTTGGGAAGGCATGGTTGACGGGTGGTATGGTTTCAGACAC CAGAACGCCCAGGGGACAGGGCAGGCCGCCGATTATAAATCCACCCAGGCCGCCATCGACC AGATTACCGGTAAATTAAACAGGCTAGTTGAAAAAACCAATACCGAGTTTGAATCCATAGA ATCTGAATTCTCCGAAATTGAACACCAGATCGGTAATGTTATCAACTGGACCAAAGACAGC ATCACCGACATATGGACTTATCAGGCTGAGCTGCTTGTCGCTATGGAGAACCAGCACACCA TCGACATGGCCGATTCTGAAATGCTGAACCTGTACGAAAGGGTGCGGAAGCAGCTACGGCA GAACGCTGAGGAGGACGGCAAGGGGTGCTTTGAAATCTACCACGCCTGCGATGATTCCTGT ATGGAGTCCATCCGTAACAACACGTACGACCACTCACAGTATAGAGAGGAAGCCCTCCTAA ACCGCCTGAATATCAACCCCGTAACCCTCTCATCTGGTTATAAAGACATCATCCTCTGGTT TAGTTTCGGCGCCTCATGTTTCGTACTGCTCGCAGTGGTGATGGGCCTGGTATTCTTCTGT CTAAAGAACGGGAATATGAGATGCACCATCTGCATT 786 ATGTATAAGATCGTGGTGATCATTGCACTCCTTGGGGCAGTCAAAGGCTTGGACAAAATTT GTTTGGGACACCACGCAGTCGCTAACGGTACAATAGTCAAAACACTGACAAATGAGCAGGA AGAAGTGACTAACGCCACAGAAACAGTGGAGTCCACAGGCATTAATCGCCTTTGTATGAAG GGTCGCAAGCATAAGGATCTGGGGAACTGTCACCCTATAGGTATGCTGATAGGGACTCCAG CCTGTGATTTACACCTGACAGGGATGTGGGACACGCTCATCGAGAGGGAAAACGCCATCGC CTACTGCTATCCTGGGGCTACAGTCAACGTCGAGGCCCTACGACAAAAAATTATGGAGAGC GGCGGGATCAATAAGATTTCCACTGGCTTTACTTATGGCTCATCTATAAACTCCGCAGGCA CAACACGCGCCTGTATGCGCAACGGCGGAAACTCATTTTACGCGGAACTGAAGTGGCTGGT TTCTAAAAGCAAGGGCCAGAATTTCCCACAGACTACAAATACCTATCGCAACACTGACACC GCAGAACACTTAATAATGTGGGGGATTCACCACCCCTCGAGCACCCAAGAGAAGAACGACC TTTATGGAACGCAGTCTCTCAGCATCAGCGTGGGATCATCCACATACCGGAACAACTTTGT GCCTGTGGTGGGAGCTCGACCACAAGTCAACGGCCAGTCTGGTAGAATTGATTTTCACTGG ACCCTTGTGCAACCTGGGGATAATATAACTTTCTCGCACAATGGTGGTTTAATAGCCCCAT CTCGCGTCAGCAAACTGATCGGTAGAGGCCTCGGAATACAGTCCGATGCACCTATCGATAA CAATTGTGAATCCAAGTGCTTCTGGAGGGGGGGATCCATTAATACTCGGCTGCCTTTCCAA AATTTGTCACCCCGCACTGTGGGCCAGTGTCCAAAGTACGTGAACAGAAGGAGCCTGATGT TGGCAACCGGGATGCGCAACGTTCCCGAACTCATCCAGGGGAGAGGTTTGTTTGGAGCTAT CGCGGGCTTTCTCGAAAACGGCTGGGAGGGGATGGTGGATGGATGGTACGGCTTTCGTCAC CAGAACGCCCAGGGAACGGGGCAAGCAGCCGATTACAAGAGCACCCAGGCCGCTATCGACC AGATTACGGGGAAGCTGAACCGCCTAGTAGAGAAGACCAACACAGAATTCGAATCTATTGA ATCAGAGTTTAGCGAAATAGAGCATCAGATCGGAAACGTGATCAATTGGACTAAAGATTCT ATCACAGATATCTGGACTTACCAGGCTGAACTGCTTGTAGCAATGGAGAATCAACACACAA TAGACATGGCCGATTCTGAGATGCTGAACCTGTACGAGCGTGTACGCAAACAGCTGAGACA GAACGCCGAAGAGGATGGTAAAGGATGTTTCGAAATCTACCATGCTTGCGACGACTCTTGC ATGGAAAGTATCCGGAACAATACATACGATCACTCCCAATATCGCGAGGAGGCGCTGCTGA ACAGACTGAACATTAACCCCGTGACTCTATCCTCAGGGTACAAGGATATCATATTATGGTT CTCTTTCGGCGCCTCCTGTTTCGTCCTGCTGGCCGTCGTAATGGGCCTTTTCTTTTTCTGT TTGAAGAATGGAAATATGCGGTGCACCATCTGTATA 787 ATGTACAAAATCGTGGTAATTATTGCTCTTCTTGGGGCTGTTAAAGGGTTGGACAAGATTT GTCTCGGGCATCACGCCGTGGCCAATGGAACGATTGTGAAGACACTGACCAACGAACAGGA GGAGGTAACTAACGCCACGGAAACTGTCGAGTCCACTGGCATCAATCGGCTCTGTATGAAG GGCCGCAAACACAAGGACTTGGGGAACTGCCACCCAATCGGCATGCTTATCGGCACACCCG CTTGTGACTTACATCTGACTGGGATGTGGGACACGCTTATAGAACGGGAAAACGCCATTGC CTACTGCTACCCAGGTGCAACTGTTAACGTCGAAGCTCTGCGCCAAAAGATCATGGAAAGC GGCGGTATCAACAAAATTAGTACGGGCTTTACCTATGGCTCAAGCATTAACTCAGCTGGCA CCACCCGTGCCTGTATGAGGAATGGAGGCAACTCCTTTTACGCTGAGCTCAAGTGGCTCGT GTCCAAGTCCAAGGGACAGAATTTCCCCCAGACTACCAATACCTATAGAAATACTGACACC GCTGAACACTTGATTATGTGGGGTATCCATCACCCTAGCTCCACTCAGGAAAAAAACGATC TATACGGCACCCAGTCGTTGTCCATCTCAGTCGGCAGTTCCACTTATCGCAACAACTTTGT GCCCGTGGTCGGAGCACGTCCTCAGGTTAATGGCCAGTCTGGCCGTATCGATTTTCACTGG ACACTGGTACAGCCTGGCGATAATATTACTTTTAGCCACAACGGGGGCCTGATCGCCCCGA GTCGTGTGTCCAAGCTTATCGGACGAGGTCTTGGGATTCAATCTGATGCCCCAATTGACAA TAACTGTGAAAGCAAATGCTTTTGGCGCGGGGGATCCATTAACACGCGGCTTCCTTTCCAG AATCTATCCCCTCGTACTGTCGGGCAATGCCCTAAGTACGTCAACCGGAGGTCCCTGATGC TGGCCACTGGCATGCGTAACGTCCCAGAGCTCATTCAGGGCAGAGGTTTATTCGGAGCAAT TGCAGGGTTCCTGGAGAACGGCTGGGAGGGAATGGTCGATGGCTGGTATGGTTTCCGCCAT CAAAACGCTCAAGGCACAGGCCAGGCGGCCGATTACAAATCGACTCAGGCGGCCATTGACC AAATCACAGGCAAACTGAATAGACTGGTGGAAAAAACAAACACCGAGTTTGAGTCTATTGA ATCTGAGTTTAGCGAAATCGAGCACCAAATCGGCAATGTTATTAACTGGACTAAGGATTCA ATTACGGATATTTGGACATACCAGGCGGAGTTATTAGTTGCCATGGAGAATCAGCACACTA TTGATATGGCTGATAGTGAGATGTTAAATTTGTACGAGAGGGTTAGGAAGCAGTTGAGGCA GAACGCGGAGGAAGACGGGAAAGGCTGCTTCGAGATTTACCACGCCTGCGACGATTCCTGC ATGGAGAGCATCCGGAATAATACCTACGACCATTCACAGTATCGAGAAGAAGCTCTATTAA ACCGTTTGAACATCAACCCAGTGACCTTAAGTAGCGGATACAAAGACATTATTCTATGGTT CTCCTTCGGCGCCTCCTGTTTCGTGTTGCTCGCCGTTGTAATGGGATTGTTTTTCTTCTGT CTGAAGAATGGAAACATGAGATGCACAATTTGTATC 788 ATGTACAAGATTGTTGTGATCATCGCCCTTCTGGGGGCCGTGAAGGGACTTGACAAAATAT GCCTCGGTCATCACGCTGTTGTGAATGGCACAATAGTTAAAACGCTGACCAACGAGCAAGA AGAGGTGACCAACGCAACCGAGACAGTGGAGAGTACAGGTCTGAACCGACTGTGCATGAAG GGCCGAAACCACAAGGACCTCGGCAATTGTCACCCCATCGGAATGTTAATTGGTACCCCCG CCTGCGATCTGCATCTGACCGGTACTTGGGATACCTTAATTGAAAGGGAAAACGCCATCGC GTACTGTTATCCCGGAGCAACCGTGAACGAGGAAGCCCTCAGACAGAAGATCATGGAGTCG GGAGGCATCAACAAGATCTCCACAGGCTTCACGTACGGCTCCTCTATTAATTCTGCCGGAA CAACTCGGGCCTGTATGCGCAACGGAGGCAACTCCTTCTACGCAGAACTGAAATGGCTTGT CAGCAAGAGCAAGGGTCAGAATTTCCCCCAAACTACCAATACTTATAGGAATACGGACACC GCAGAACACCTGATAATGTGGGGCATTCATCATCCCTCTTCAACTCAGGAGAAAAATGATT TGTATGGGACTCAATCCTTATCAATCTCCGTGGGTAGCAGCACCTATCAGAATAACTTTGT TCCAGTCGTAGGGGCCCGGCCTCAGGTGAACGGGCAGTCAGGCAGAATTGATTTCCACTGG ACCCTTGTGCAACCCGGAGACAACATTACCTTTAGTCACAATGGCGGTCTCATCGCCCCTT CCAGAGTGTCTAAACTGATCGGTCGGGGCCTGGGCATCCAGAGCGACGCACCAATCGACAA TAATTGCGAGAGTAAGTGCTTCTGGAGAGGTGGTAGTATCAATACTAGGCTCCCATTCCAA AATTTATCGCCTAGGACCGTCGGACAGTGTCCCAAATATGTAAATAAAAGGTCCTTAATGC TTGCGACGGGAATGCGTAACGTTCCTGAACTGATGCAGGGCAGAGGCCTATTTGGCGCAAT AGCCGGTTTTATCGAGAACGGCTGGGAGGGGATGGTGGACGGTTGGTATGGATTTAGGCAC CAAAATGCCCAGGGAACTGGGCAGGCGGCGGATTACAAGAGCACACAAGCTGCTATCGACC AGATCACGGGCAAACTGAATCGATTGATTGAAAAGACCAACACTGAGTTTGAATCAATTGA GAGTGAGTTTTCAGAGATTGAACACCAGATCGGGAACGTGATAAACTGGACTAAAGATTCC ATCACTGACATCTGGACATATCAGGCGGAGCTCCTGGTGGCCATGGAGAACCAACACACCA TCGACATGGCAGACTCTGAAATGTTAAATCTGTACGAGAGAGTCAGGAAACAGCTGCGCCA GAATGCCGAGGAAGATGGCAAGGGTTGCTTCGAGATCTACCACGCATGTGACGACAGCTGC ATGGAGTCAATTCGCAACAACACCTACGACCACTCCCAATACAGGGAGGAGGCACTGCTTA ACAGGCTGAACATTAATCCGGTCACCCTCTCTAGCGGCTATAAGGATATTATTCTGTGGTT CAGTTTTGGCGCTTCTTGTTTTGTCCTGCTGGCAGTGGTGATGGGCCTGGTCTTCTTTTGC CTAAAAAATGGGAATATGAGGTGCACCATCTGTATT 789 ATGTATAAAATTGTGGTCATCATTGCTCTGCTGGGTGCAGTAAAGGGGCTGGACAAAATTT GTCTGGGACACCATGCCGTTGCCAACGGAACAATCGTGAAGACGCTTACTAACGAACAGGA AGAAGTTACCAACGCTACCGAAACCGTCGAATCCACGGGTATCAACAGGCTGTGTATGAAA GGGAGGAAGCACAAAGATTTGGGGAACTGCCACCCAATCGGCATGTTGATTGGCACTCCCG CCTGTGATCTGCATTTAACTGGTATGTGGGATACCCTGATCGAGCGAGAAAATGCTATTGC ATACTGTTATCCAGGCGCGACTGTGAATGTCGAAGCTCTGCGACAGAAAATCATGGAATCC GGCGGTATCAATAAAATTTCGACAGGCTTCACATATGGGAGTTCTATTAACTCTGCCGGGA CCACCAGAGCCTGCATGCGCAACGGAGGAAATAGCTTCTACGCTGAGTTAAAGTGGCTAGT CTCTAAATCTAAAGGACAAAACTTCCCACAGACCACTAACACCTACCGGAATACCGATACC GCGGAACACTTAATTATGTGGGGGATCCACCACCCAAGCTCTACGCAGGAAAAGAACGATC TCTACGGGACTCAGTCTTTATCAATTTCCGTGGGCTCCTCTACATACCGCAATAATTTCGT GCCCGTGGTTGGCGCTAGGCCTCAGGTAAACGGGCAGAGTGGAAGGATAGATTTTCACTGG ACCCTGGTTCAGCCGGGCGACAACATCACTTTCAGTCACAATGGCGGCCTTATCGCTCCCA GCCGGGTGTCTAAATTGATCGGCAGGGGACTGGGTATCCAGTCGGACGCTCCAATTGACAA CAATTGTGAGTCAAAGTGCTTTTGGCGAGGGGGGAGCATCAACACTCGCCTCCCTTTCCAA AACCTGTCTCCTCGGACGGTCGGACAATGCCCTAAGTACGTAAACAGGCGGTCGCTGATGC TGGCCACTGGGATGAGAAACGTGCCAGAACTTATTCAGGGCCGTGGCTTGTTCGGCGCAAT CGCTGGGTTTCTTGAAAATGGCTGGGAAGGGATGGTGGATGGTTGGTATGGGTTCCGACAT CAGAACGCTCAGGGCACTGGGCAGGCCGCTGATTATAAGTCCACCCAGGCAGCTATAGACC AAATAACAGGGAAACTAAATCGCCTGGTCGAAAAGACAAATACAGAGTTCGAATCTATCGA GAGCGAATTCTCAGAAATCGAGCACCAGATTGGGAATGTGATTAATTGGACCAAGGATAGT ATCACAGATATCTGGACATACCAGGCAGAACTGTTGGTTGCCATGGAAAACCAGCACACCA TTGATATGGCAGATTCAGAGATGCTTAACCTGTATGAGAGAGTGCGAAAGCAGCTGCGCCA GAACGCAGAAGAGGATGGAAAGGGGTGCTTCGAAATTTACCACGCTTGCGATGATAGCTGT ATGGAGTCAATAAGAAACAACACCTATGACCACAGCCAGTACAGGGAGGAGGCACTACTTA ATAGGCTGAATATCAATCCAGTTACTTTGTCCAGCGGCTATAAGGACATTATACTGTGGTT TAGCTTTGGGGCGTCCTGCTTTGTGCTCCTGGCTGTAGTGATGGGGCTATTTTTCTTCTGT TTAAAGAACGGTAATATGCGGTGCACAATCTGTATC 790 ATGTACAAAATAGTGCTGGTGCTCGCCCTCCTCGGTGCTGTGCATGGTCTTGACAAGATAT GTCTCGGACATCACGCCGTCCCGAACGGAACTATTGTGAAAACCCTAACCAACGAGAAGGA AGAGGTGACTAACGCGACCGAAACTGTGGAAAGCAAGAGTCTGGATAAACTGTGTATGAAG AATAGGAATTACAAGGACCTGGGCAATTGTCATCCTATTGGGATGGTGGTCGGTACCCCCG CTTGTGATCTTCATCTGACCGGAACCTGGGATACCCTGATAGAGCGCGACAATTCAATTGC GTATTGCTACCCCGGTGCCACAGTTAGCGAGGAAGCCTTGCGCCAGAAGATCATGGAGAGT GGCGGCATAGATAAAATCAGCACCGGATTCACGTACGGGAGTAGTATCAATTCAGCCGGCA CAACAAAAGCCTGCATGAGAAATGGCGGAAACTCCTTTTATTCTGAACTGAAATGGCTCGT GTCCAAGAACAAGGGCCAGAACTTTCCTCAGACGACCAATACTTATCGCAACACAGATTCC GTCGAACATTTGATCATTTGGGGCATTCACCATCCTAGCTCTACCCAGGAGAAAAACGATC TGTACGGCACCCAAAGCCTGTCCATTAGCGTCGGGTCCAGTACATACCAGAACAACTTCGT GCCAGTCGTCGGGGCGCGGCCGCAGGTCAACGGCCAGTCAGGGAGAATAGACTTTCATTGG ACCATGGTGCAGCCCGGGGACAACATTACTTTTTCCCATAATGGAGGCCTGATCGCACCAA ATCGGGTCTCTAAGCTGAAAGGGAGAGGTCTCGGGATCCAGTCCGGAGCATCTGTGGACAA CGACTGTGAATCCAAATGCTTCTGGAAGGGTGGGTCTATCAATACCAAGCTCCCCTTTCAG AATCTCTCGCCTAGGACCGTGGGACAGTGCCCAAAATACGTGAACAAAAAAAGTCTCCTCC TGGCTACTGGTATGCGGAATGTCCCAGAGGTTGCACAGGGGCGAGGCCTGTTCGGTGCCAT AGCGGGTTTTATTGAGAACGGTTGGGAGGGAATGGTGGATGGCTGGTATGGGTTTCGGCAC CAAAATGCACAGGGCACAGGTCAGGCCGCCGATTATAAGAGCACACAGGCAGCCATTGATC AGATTACAGGGAAGCTGAATCGACTGATAGAAAAAACAAATACCGAGTTTGAGTCCATTGA AAGCGAATTTAGCGAGATTGAGCACCAGATAGGGAATGTCATCAATTGGACCAAAGATTCA ATCACTGATATTTGGACTTACCAGGCTGAGCTGCTGGTTGCAATGGAAAATCAGCACACAA TTGACATGGCCGACAGCGAGATGCTGAACCTCTACGAGAGAGTGCGTAAACAGCTGCGCCA GAACGCAGAAGAGGATGGGAAGGGATGTTTCGAAATTTATCACAAGTGTGATGACAACTGT ATGGAGAGCATTCGAAACAACACGTACGACCATACTCAGTATCGGGAGGAAGCCCTGTTGA ATCGCCTCAATATTAATCCCGTGAAACTCTCATCCGGTTATAAAGACGTCATACTGTGGTT TTCCTTCGGGGCCAGCTGCTTCGTACTGCTGGCCGTCATTATGGGCCTTGTTTTTTTCTGT CTGAAAAATGGAAACATGAGGTGTACCATCTGTATT 791 ATGTATAAAATCGTGGTGATCATCGCACTGCTGGGTGCGGTTAAGGGGCTCGACAAGATTT GCCTGGGACACCATGCAGTGGCAAATGGCACTATTGTCAAAACACTTACTAACGAGCAGGA GGAAGTGACAAACGCCACGGAGACCGTTGAGAGCACGGGCATCAATCGGCTGTGCATGAAA GGCAGGAAGCATAAGGACCTCGGCAACTGCCATCCTATTGGTATGCTGATTGGCACGCCCG CTTGCGATCTGCATCTGACCGGAATGTGGGATACGCTTATAGAGAGAGAGAACGCGATTGC CTACTGCTACCCCGGCGCTACAGTCAATGTCGAAGCTCTGCGCCAAAAAATTATGGAATCT GGCGGGATTAACAAGATCTCCACTGGCTTCACGTATGGATCTTCAATAAACTCAGCCGGCA CCACACGGGCCTGCATGCGCAATGGGGGAAACTCATTCTATGCTGAACTGAAATGGCTTGT CTCAAAATCTAAGGGGCAGAATTTTCCTCAAACTACCAACACCTACAGGAATACGGATACC GCTGAGCACCTGATCATGTGGGGTATCCACCACCCTTCGTCCACCCAGGAAAAAAATGACC TATATGGTACCCAGTCACTGAGTATCAGCGTAGGCAGTTCTACATATCGTAACAACTTTGT CCCAGTAGTCGGGGCCCGCCCTCAAGTGAACGGCCAATCTGGACGTATTGATTTCCACTGG ACACTGGTGCAACCCGGAGACAACATCACTTTCTCCCACAACGGAGGGCTGATAGCCCCCT CCAGGGTCTCCAAGTTGATCGGACGTGGACTTGGGATACAGTCTGATGCCCCAATTGATAA TAACTGTGAGTCTAAATGCTTCTGGAGGGGGGGCAGTATCAATACACGCCTGCCTTTCCAG AACCTGTCGCCACGGACAGTTGGACAGTGTCCAAAATATGTGAACCGCAGGTCGCTGATGT TGGCAACCGGAATGAGGAATGTGCCCGAGCTGATTCAGGGTCGGGGATTATTTGGCGCCAT CGCAGGGTTCCTGGAAAATGGATGGGAAGGCATGGTGGATGGATGGTACGGCTTTAGACAC CAAAACGCCCAGGGAACAGGGCAAGCAGCAGACTACAAATCCACGCAAGCTGCTATAGACC AGATTACTGGTAAGCTCAACCGTCTCGTTGAGAAAACAAATACGGAATTTGAGAGTATCGA GTCAGAGTTTTCTGAAATCGAACATCAAATAGGGAATGTAATTAATTGGACAAAAGACTCA ATCACTGACATATGGACCTATCAGGCTGAACTGCTAGTTGCAATGGAGAATCAACATACCA TCGACATGGCTGACAGCGAGATGCTGAATTTGTACGAACGGGTCAGAAAACAACTGCGGCA GAATGCTGAGGAAGATGGAAAGGGGTGTTTCGAAATATATCACGCTTGTGATGACTCTTGC ATGGAATCCATCCGGAATAATACCTACGATCACTCGCAGTATCGAGAGGAGGCCCTGCTGA ATCGCTTAAACATTAATCCAGTGACACTGTCTTCCGGGTATAAAGATATCATTCTGTGGTT TTCCTTTGGCGCATCCTGCTTCGTATTACTAGCCGTTGTCATGGGATTGTTTTTCTTTTGT CTGAAAAACGGGAACATGCGGTGTACCATTTGTATT 792 ATGTACAAGATCGTGGTCATCATCGCTCTGTTGGGCGCCGTGAAAGGGCTTGATAAGATCT GTCTTGGGCACCACGCCGTGGCCAACGGGACCATTGTGAAAACCCTCACGAACGAGCAGGA GGAAGTGACAAACGCAACTGAGACCGTTGAGTCAACCGGTATTAATCGCTTGTGCATGAAA GGACGAAAGCACAAGGACTTGGGCAACTGCCATCCAATTGGGATGCTGATCGGTACCCCAG CATGTGATCTGCATTTAACAGGCATGTGGGATACCCTTATTGAGCGAGAAAATGCCATCGC GTATTGCTATCCTGGAGCCACTGTGAATGTGGAGGCACTGCGTCAGAAGATTATGGAATCT GGCGGGATCAATAAAATAAGCACCGGCTTTACATACGGCAGCTCGATTAATTCCGCTGGCA CCACTAGAGCTTGCATGCGCAATGGCGGCAACTCATTCTATGCCGAGCTGAAGTGGTTGGT GAGTAAGAGCAAAGGGCAGAACTTTCCTCAGACCACCAACACCTATCGAAATACGGACACA GCTGAACACCTTATAATGTGGGGGATCCACCACCCGTCATCTACCCAGGAAAAGAACGACT TATACGGAACACAGTCTCTGTCCATCTCGGTTGGATCCTCTACTTACCGAAATAATTTTGT GCCCGTCGTGGGGGCCAGACCCCAGGTAAACGGACAGTCTGGCAGGATCGATTTCCATTGG ACTCTGGTCCAGCCCGGAGATAATATCACCTTTAGTCACAACGGTGGACTGATCGCTCCCA GTAGAGTGTCCAAGCTGATAGGCAGAGGGCTTGGAATCCAAAGCGACGCCCCAATCGATAA TAACTGCGAAAGCAAGTGTTTCTGGCGGGGCGGATCCATCAACACCAGGCTTCCCTTCCAG AACTTGTCCCCAAGGACTGTTGGACAGTGCCCAAAGTATGTTAATCGACGGAGTCTGATGC TCGCTACTGGCATGAGAAACGTACCCGAGCTGATACAAGGGCGCGGGCTGTTCGGCGCAAT AGCCGGATTCCTGGAGAACGGATGGGAGGGTATGGTGGACGGCTGGTATGGCTTTCGGCAT CAGAATGCCCAGGGTACTGGTCAGGCAGCCGATTATAAGTCAACCCAGGCTGCCATCGATC AGATTACAGGGAAACTGAATCGGCTGGTGGAAAAAACCAATACCGAATTTGAGTCCATTGA ATCTGAATTCAGCGAGATCGAGCACCAGATCGGTAATGTCATAAATTGGACTAAGGATTCC ATCACAGATATCTGGACATACCAAGCTGAGCTGCTTGTGGCCATGGAAAACCAGCATACAA TAGACATGGCCGACAGTGAGATGCTAAATCTGTATGAGAGAGTGAGAAAACAACTAAGACA GAATGCTGAGGAGGACGGCAAAGGTTGTTTTGAGATCTACCACGCTTGCGACGACTCGTGT ATGGAATCCATACGCAACAATACTTACGACCACTCTCAGTACCGCGAGGAAGCTTTACTTA ACCGCCTGAATATTAACCCTGTTACCTTATCCAGTGGGTACAAAGACATAATATTGTGGTT CAGTTTTGGCGCGTCGTGTTTTGTTCTCCTGGCCGTTGTGATGGGCCTGTTTTTTTTCTGC CTGAAGAACGGGAATATGCGCTGTACTATCTGCATA 793 ATGTACAAGATAATCGTCATTATCGCACTGTTGGGCGCCGTTAAAGGACTGGATAAAATCT GCCTGGGCCATCACGCAGTCGCTAACGGTACAATCGTGAAAACTCTGACCAATGAGCAGGA GGAAGTCACCAACGCAACCGAAACCGTAGAGTCCACCGGCATCAACCGGCTCTGTATGAAG GGCCGCAAGCATAAAGACCTGGGTAACTGCCACCCCATAGGCATGCTTATTGGCACTCCGG CATGCGACTTGCACCTGACGGGGACCTGGGACACATTGATTGAACGGGAAAATGCTATTGC TTATTGCTATCCTGGAGCCACAGTGAATGTGGAGGCTCTCCGCCAAAAGATCATGGAATCT GGGGGGATAGATAAGATTAGTACTGGGTTTACGTATGGGAGTTCTATCAACAGCGCCGGGA CCACAAGAGCCTGTATGAGAAACGGAGGAAACAGCTTTTACGCAGAGTTGAAATGGCTTGT TAGTAAATCTAAGGGGCAGAATTTCCCTCAGACCACGAACACTTACAGGAATACGGATACT GCGGAGCACCTTATTATGTGGGGCATCCATCATCCCTCCTCTACTCAGGAGAAAAACGACC TCTATGGCACTCAATCCTTGTCCATCTCCGTCGGTTCCTCAACCTATAGGAACAACTTTGT GCCAGTTGTAGGCGCAAGGCCACAGGTTAACGGGCAGAGCGGTCGCATCGACTTCCACTGG ACCCTGGTGCAGCCAGGCGATAACATCACCTTTTCACACAACGGCGGGCTGATCGCACCTT CCCGAGTGTCTAAGCTGATAGGGAGGGGCCTCGGCATCCAGTCTGACGCACCAATTGACAA TAATTGTGAGTCCAAGTGTTTTTGGCGCGGAGGTTCAATTAACACGCGCCTGCCCTTTCAG AATCTGTCTCCCCGTACTGTGGGCCAGTGTCCAAAGTATGTTAATAGGCGGTCCCTCATGC TGGCTACGGGAATGAGAAACGTGCCTGAGCTGATACAGGGCCGAGGACTATTCGGGGCGAT CGCCGGCTTTTTAGAAAACGGGTGGGAGGGCATGGTCGACGGATGGTATGGCTTCAGACAC CAGAATGCGCAGGGGACTGGCCAGGCTGCTGACTATAAGAGTACCCAGGCCGCTATAGACC AGATCACGGGTAAGCTGAATCGTCTGGTTGAAAAGACTAATACTGAATTTGAAAGCATCGA AAGCGAGTTTAGCGAAATTGAGCATCAGATCGGGAACGTCATTAATTGGACTAAAGACTCC ATTACTGATATCTGGACGTACCAGGCTGAGTTGTTAGTGGCCATGGAAAATCAGCATACCA TTGATATGGCAGATAGCGAAATGCTGAATCTGTACGAGAGAGTTCGTAAGCAGCTGCGCCA GAACGCTGAAGAGGACGGAAAGGGATGCTTTGAGATCTACCACGCCTGCGACGACAGCTGT ATGGAATCGATCCGGAACAACACCTATGACCACTCCCAGTATAGGGAAGAAGCCCTGTTAA ACCGCCTGAATATTAATCCCGTCACTCTGTCATCCGGCTATAAGGACATAATTCTTTGGTT TAGCTTCGGCGCTAGTTGCTTTGTGCTACTGGCTGTCGTGATGGGCCTCTTTTTTTTTTGC CTTAAAAATGGCAATATGAGGTGTACAATCTGTATC 794 ATGTATAAGATCGTCGTAATCATCGCCCTGCTGGGCGCTGTTAAGGGGCTGGATAAGATCT GCCTAGGCCACCATGCCGTAGCCAATGGTACAATCGTTAAGACATTAACCAATGAGCAGGA GGAGGTTACAAACGCTACCGAAACCGTTGAGAGCACCGGGATTAACCGACTCTGTATGAAG GGTAGGAAACATAAGGACCTCGGCAATTGCCATCCTATTGGCATGCTCATAGGGACCCCAG CGTGTGACTTGCACCTCACTGGAATGTGGGACACTCTGATCGAGAGGGAAAATGCCATAGC TTATTGTTACCCAGGAGCCACAGTGAATGTGGAAGCCCTGAGACAGAAGATCATGGAGTCC GGCGGAATCAACAAGATCAGCACTGGTTTCACCTATGGGAGTAGCATAAACAGCGCTGGTA CTACCCGAGCATGCATGCGGAATGGAGGCAATAGCTTTTACGCTGAACTGAAATGGCTGGT CTCAAAATCGAAAGGGCAGAATTTTCCTCAGACGACAAATACCTATCGCAATACGGACACC GCAGAACACCTGATTATGTGGGGTATCCACCATCCTAGCTCCACACAGGAGAAAAATGATC TGTACGGAACCCAGTCCCTGTCTATCTCCGTGGGATCCTCCACTTACCGGAACAATTTTGT TCCTGTCGTGGGGGCTCGGCCGCAAGTGAACGGTCAGAGCGGACGAATTGATTTCCACTGG ACTCTGGTGCAGCCTGGGGACAATATCACGTTCTCCCATAACGGAGGACTGATCGCCCCCA GCCGCGTGAGCAAGTTGATTGGGCGCGGCCTTGGAATTCAGTCAGATGCGCCAATAGATAA TAATTGTGAATCTAAGTGTTTCTGGAGGGGAGGCTCCATCAATACCCGGCTCCCTTTCCAA AATTTGTCCCCGAGAACAGTGGGTCAGTGCCCAAAATATGTGAACCGCCGATCTCTGATGC TGGCCACCGGCATGAGGAACGTGCCTGAGCTGATTCAGGGTAGAGGCCTGTTTGGAGCCAT CGCCGGCTTTTTAGAGAACGGCTGGGAAGGAATGGTCGACGGATGGTATGGCTTCAGGCAC CAGAACGCCCAAGGGACTGGCCAGGCGGCTGACTACAAGTCCACTCAAGCGGCTATTGACC AAATTACAGGAAAGCTGAATAGACTCGTTGAAAAAACTAATACAGAGTTTGAAAGTATAGA ATCTGAGTTCTCAGAAATAGAGCATCAGATTGGAAACGTGATCAACTGGACTAAAGACTCT ATCACCGATATTTGGACGTATCAGGCGGAGTTGCTCGTCGCGATGGAGAACCAACACACAA TAGATATGGCTGATTCTGAGATGCTGAACTTGTACGAACGGGTGCGTAAACAACTGCGCCA AAATGCTGAGGAGGACGGGAAGGGGTGTTTTGAGATCTACCATGCTTGCGACGATAGCTGC ATGGAGTCAATTCGAAATAACACGTATGACCACAGCCAGTACAGGGAAGAGGCCCTGCTGA ACAGGCTGAATATAAATCCCGTTACCCTCTCCTCTGGATACAAAGACATCATCCTCTGGTT TTCATTCGGAGCTAGTTGCTTCGTACTACTAGCTGTTGTAATGGGCCTGTTCTTCTTCTGT CTCAAGAATGGTAACATGCGGTGTACGATCTGCATC 795 ATGTATAAGATCGTGGTGATCATTGCCCTCTTGGGCGCCGTGAAGGGTCTGGATAAAATAT GTCTTGGTCACCACGCTGTGGCTAATGGTACCATCGTGAAGACGCTTACCAACGAACAAGA GGAAGTGACAAATGCTACCGAGACCGTGGAGTCTACCGGGATCAACCGACTGTGCATGAAA GGACGAAAGCACAAAGACCTCGGCAATTGCCACCCTATTGGGATGTTGATTGGCACTCCAG CTTGCGACCTTCACCTGACCGGAATGTGGGACACGCTCATCGAGCGCGAGAACGCCATTGC CTACTGCTACCCCGGGGCCACCGTTAACGTGGAAGCACTTAGGCAAAAAATTATGGAATCC GGTGGAATAAACAAGATTAGCACTGGTTTCACTTATGGGAGTAGTATTAACTCTGCCGGGA CAACCAGGGCTTGTATGAGAAATGGCGGCAATTCATTTTACGCAGAGCTCAAGTGGCTGGT TTCAAAAAGTAAAGGGCAGAATTTCCCGCAAACCACTAATACCTACAGGAACACAGACACG GCCGAGCACCTGATCATGTGGGGTATTCACCACCCTAGCAGCACGCAAGAGAAAAATGACC TTTATGGAACCCAGAGCCTCAGTATTTCAGTGGGAAGCAGCACGTACCGTAATAATTTTGT TCCGGTAGTCGGCGCCCGACCCCAGGTGAACGGGCAGTCGGGACGAATCGACTTTCATTGG ACGCTTGTGCAGCCTGGCGACAACATCACCTTTAGCCACAATGGCGGCCTGATTGCTCCCA GCCGCGTCAGCAAGCTGATCGGGCGCGGACTGGGCATTCAGTCTGATGCCCCTATTGATAA CAACTGCGAGAGCAAGTGTTTTTGGCGGGGAGGCTCCATAAATACTCGCTTACCTTTCCAG AACCTCAGTCCAAGGACCGTAGGGCAGTGTCCTAAGTATGTTAACAGAAGGAGTCTCATGT TAGCCACAGGAATGCGCAATGTACCAGAACTCATTCAGGGCAGGGGACTCTTTGGTGCAAT TGCTGGGTTTCTGGAGAACGGTTGGGAAGGTATGGTCGACGGCTGGTACGGCTTTCGACAT CAAAATGCACAGGGCACAGGCCAGGCGGCTGATTATAAATCCACTCAGGCCGCCATCGACC AAATCACAGGAAAGCTCAACCGTCTGGTCGAGAAGACCAATACTGAGTTCGAAAGCATCGA GTCAGAGTTTAGCGAGATTGAGCATCAGATTGGCAATGTCATCAACTGGACTAAAGATAGC ATAACCGATATTTGGACGTACCAAGCAGAGCTACTTGTTGCTATGGAGAATCAGCATACCA TTGATATGGCCGATAGCGAGATGCTGAATCTGTATGAGAGAGTGAGAAAGCAGTTGAGACA AAACGCGGAGGAGGATGGGAAGGGCTGTTTCGAGATCTACCACGCCTGCGACGACTCCTGT ATGGAGTCTATACGCAACAACACATACGACCACAGCCAGTATAGGGAGGAAGCCTTGCTGA ATAGGCTGAATATCAATCCTGTAACGCTGTCGAGTGGGTACAAAGACATCATTTTATGGTT CAGTTTTGGAGCCTCTTGTTTCGTTTTGCTGGCCGTCGTCATGGGACTATTTTTTTTTTGT TTAAAGAACGGGAACATGAGATGCACTATTTGCATC 796 ATGTACAAGATTGTGTTGGTCCTAGCCCTCCTCGGCGCTGTGCATGGGCTGGATAAGATCT GCCTTGGGCACCACGCCGTGCCTAATGGCACTATCGTGAAAACACTCACAAACGAAAAAGA GGAAGTAACAAATGCCACCGAGACTGTGGAAAGCAAGAGCCTTGATAAACTCTGTATGAAA AACAGAAATTATAAAGATTTAGGCAACTGTCATCCCATTGGTATGGTTGTGGGAACGCCCG CTTGTGATCTGCATTTAACGGGTACATGGGATACCCTCATCGAGCGAGATAACTCAATCGC CTACTGCTACCCGGGCGCCACTGTGTCAGAGGAAGCCTTGAGACAGAAGATTATGGAATCC GGCGGTATTGACAAGATTTCTACCGGGTTTACGTATGGGTCTTCCATAAACTCCGCAGGCA CCACAAAGGCATGCATGAGAAATGGTGGTAATTCTTTCTACTCAGAGCTTAAATGGCTGGT GTCTAAGAACAAAGGCCAGAACTTTCCCCAGACGACCAACACATACCGTAACACGGACAGC GTCGAGCACCTGATCATCTGGGGCATTCACCATCCTTCCTCAACTCAGGAGAAAAACGATC TCTATGGTACCCAAAGCCTCTCTATTTCAGTCGGATCAAGCACATACCAGAACAACTTTGT GCCCGTCGTTGGAGCCAGGCCACAGGTGAACGGCCAGAGTGGTCGAATTGATTTTCACTGG ACAATGGTGCAACCTGGGGATAATATCACATTCAGCCATAATGGTGGTCTGATCGCCCCAA ATAGAGTTTCAAAGCTTAAGGGCAGGGGTCTGGGGATTCAAAGCGGTGCTTCCGTCGATAA TGACTGTGAGTCAAAATGCTTTTGGAAGGGGGGCAGCATCAATACAAAGCTACCGTTTCAG AACCTCAGTCCCAGGACAGTTGGGCAGTGTCCTAAGTATGTGAATAAAAAATCCTTACTGT TGGCCACTGGAATGAGAAACGTTCCAGAGGTAGCTCAGGGCCGTGGTCTCTTTGGGGCCAT CGCCGGCTTTATTGAAAACGGGTGGGAAGGAATGGTTGATGGGTGGTATGGGTTCAGGCAT CAGAACGCCCAGGGCACTGGACAAGCAGCTGACTATAAGAGCACACAGGCTGCTATTGACC AGATTACTGGAAAACTGAATAGGTTGATAGAGAAGACCAACACTGAGTTCGAGTCTATCGA GTCAGAGTTTTCAGAAATCGAGCATCAGATCGGTAACGTAATCAACTGGACCAAGGACTCA ATAACCGACATCTGGACATATCAAGCCGAGTTGCTGGTAGCTATGGAGAATCAACATACTA TCGACATGGCTGATTCCGAAATGCTCAACTTGTATGAGCGCGTGCGTAAGCAGTTGAGACA GAATGCTGAGGAAGATGGCAAGGGCTGCTTCGAGATTTACCACAAGTGTGACGATAATTGT ATGGAGAGCATTCGAAACAACACTTACGACCACACCCAATACCGCGAGGAAGCCCTGTTGA ATCGGCTCAACATCAATCCCGTAAAGTTGTCCAGTGGTTATAAAGACGTCATCTTATGGTT TAGTTTTGGAGCTTCTTGTTTTGTGCTCCTGGCAGTCATTATGGGACTGGTATTCTTCTGC CTGAAAAATGGGAATATGAGATGCACTATCTGTATC 797 ATGTATAAAATTGTCGTGATTATTGCTCTGCTCGGTGCCGTTAAGGGACTCGATAAGATCT GCTTAGGACATCACGCTGTAGTGAACGGCACAATCGTGAAAACACTCACGAACGAGCAGGA AGAGGTCACAAACGCCACAGAAACTGTCGAGAGCACCGGTCTAAACCGACTGTGTATGAAA GGAAGGAATCATAAGGACCTAGGCAATTGTCACCCAATCGGAATGCTTATCGGCACCCCTG CATGCGATTTGCACCTGACAGGTACATGGGATACGCTGATCGAGCGCGAGAATGCCATCGC CTATTGTTACCCCGGTGCAACCGTAAACGAGGAGGCCCTGAGGCAAAAGATAATGGAGTCA GGCGGCATAAATAAGATTAGCACCGGTTTTACCTATGGGAGCAGTATAAATAGTGCCGGTA CTACGCGCGCATGTATGCGCAATGGGGGCAACTCTTTTTACGCCGAACTCAAGTGGCTAGT GTCAAAATCGAAGGGCCAGAACTTTCCACAGACCACTAACACTTATAGGAACACGGACACA GCCGAACATTTAATAATGTGGGGTATCCATCACCCAAGTTCCACTCAGGAGAAAAACGATT TATACGGAACTCAGTCGCTGTCAATCAGCGTAGGGAGCTCAACATACCAGAACAACTTTGT TCCAGTGGTGGGCGCACGTCCCCAGGTGAACGGTCAAAGCGGCCGGATAGATTTTCACTGG ACCCTGGTGCAGCCTGGAGATAATATTACTTTTAGTCACAACGGTGGCCTAATCGCACCCA GTCGTGTATCGAAGCTTATCGGACGGGGCCTCGGGATACAGTCTGATGCTCCCATAGACAA CAACTGTGAGTCTAAGTGCTTTTGGCGGGGCGGGTCTATTAACACCAGGCTCCCATTTCAG AACCTCAGTCCTCGGACCGTGGGTCAGTGTCCGAAGTATGTTAATAAGCGTTCTCTCATGC TCGCCACTGGAATGAGGAACGTGCCAGAGCTAATGCAGGGAAGAGGACTGTTCGGGGCCAT AGCCGGCTTCATTGAAAATGGCTGGGAGGGTATGGTTGACGGATGGTACGGCTTCCGACAC CAGAATGCTCAAGGCACAGGCCAGGCTGCAGATTATAAATCAACACAGGCTGCTATTGACC AAATCACTGGCAAGCTCAATCGATTAATTGAAAAAACAAATACCGAGTTTGAAAGCATCGA GAGTGAATTTTCCGAGATCGAACACCAAATCGGAAACGTGATCAACTGGACCAAGGACTCT ATCACCGATATATGGACCTATCAGGCAGAACTTTTAGTTGCCATGGAGAACCAGCATACCA TTGATATGGCCGACAGCGAAATGCTGAACTTGTATGAGCGGGTCCGGAAACAATTACGCCA GAATGCCGAGGAAGACGGAAAAGGGTGCTTTGAGATCTATCATGCTTGCGACGACTCTTGT ATGGAGTCAATCAGAAATAATACTTATGACCATAGTCAGTATAGGGAAGAGGCGCTGCTCA ACAGACTAAATATCAACCCCGTTACGCTGAGCTCCGGTTATAAGGACATCATTCTTTGGTT TTCCTTTGGCGCAAGCTGCTTTGTTCTGCTAGCTGTAGTGATGGGACTCGTCTTTTTCTGC CTGAAGAACGGAAACATGCGCTGTACAATCTGTATT 798 ATGTATAAGATCGTTGTGATCATCGCCCTGCTGGGCGCCGTGAAAGGGCTGGACAAGATTT GTCTGGGTCACCACGCCGTCGCCAACGGGACAATTGTTAAAACACTGACTAACGAGAAGGA GGAGGTGACTAACGCAACCGAGACAGTTGAGTCCACAGGATTGAATCGGCTTTGTATGAAA GGCCGGAAGCACAAAGACCTGGGAAACTGCCACCCTATAGGGATGCTGATCGGAAGTCCTG CTTGTGATCTACACCTGACAGGTACTTGGGACACACTGATCGAGCGGGAGAATGCCATTGC TTACTGCTACCCAGGAGCCACCGTGAATGGTGAAGCTCTGAGACAGAAGATTATGGAATCC GGAGGCATTGATAAAATCTCTACAGGATTTACATACGAGTCCTCAATCAATTCAGCTGGCA CAACTCGAGCATGTATGCGCAATGGCGGGAATAGTTTTTATGCCGAGCTCAAGTGGCTCGT CTCTAAAAGCAAGGGGCAGAACTTTCCCCAGACCACGAACACCTATAGAAATACCGATACA GCCGAGCATCTTATTATGTGGGGCATACATCATCCCTCCTCTACACAAGAGAAGAATGATC TTTACGGAACGCAGTCCCTCTCGATCAGCGTGGGAAGCTCCACATATAGGAACAATTTTGT TCCCGTGGTTGGCGCTCGTCCTCAGGTGAACGGACAGAGTGGCCGAATCGACTTTCACTGG ACCCTTGTTCAGCCCGGCGACAACATAACGTTTTCGCATAATGGCGGCCTCATTGCACCTT CCCGTGTCAGCAAACTGATTGGCCGCGGGCTGGGCATCCAATCTGACGCTCCCATCGATAA CAACTGCGAATCAAAATGCTTCTGGAGGGGAGGGTCTATTAATACTCGGCTGCCATTCCAA AACCTTTCCCCCCGGACAGTTGGCCAGTGTCCGAAATATGTGAACAAACGGAGTTTGATGC TCGCTACCGGGATGCGGAACGTGCCTGAATTGATGCAGGGAAGAGGTCTTTTCGGCGCCAT TGCCGGCTTCTTGGAAAATGGTTGGGAAGGGATGGTCGACGGATGGTATGGATTTCGGCAT CAGAACGCTCAAGGCACTGGGCAGGCAGCTGATTATAAATCAACCCAGGCTGCCATTGACC AGATAACTGGCAAACTCAACAGGCTGGTGGAGAAGACCAACACCGAATTCGAGAGTATTGA GTCTGAATTCAGCGAGATCGAGCACCAGATAGGGAACGTTATTAACTGGACCAAGGATTCT ATTACGGACATTTGGACATACCAAGCTGAGCTCTTAGTGGCCATGGAGAATCAGCATACCA TTGACATGGCCGATTCTGAGATGCTTAATCTCTATGAGAGGGTGAGAAAGCAGCTGCGGCA GAATGCCGAAGAAGATGGCAAGGGGTGCTTTGAGATTTACCACGCTTGCGATGATTCATGT ATGGAATCTATTCGCAATAACACCTACGATCATTCTCAGTATCGGGAGGAAGCCCTGCTGA ATCGCCTGAACATTAATCCCGTGACACTTTCAAGTGGTTACAAGGACATAATTCTATGGTT CAGTTTTGGGGCTAGTTGTTTTGTGCTCCTAGCCGTTGTGATGGGTCTTGTCTTCTTTTGT TTGAAGAACGGAAATATGCGGTGTACAATCTGTATA 799 ATGTACAAGATCGTGGTGATCATTGCGCTCCTGGGCGCCGTCAAGGGACTGGACAAGATCT GCCTGGGCCATCACGCTGTGGCAAATGGGACAATCGTGAAAACGCTGACTAACGAGCAAGA GGAGGTGACAAATGCGACGGAGACAGTGGAATCGACTGGGATTAACCGACTGTGTATGAAA GGAAGAAAACATAAAGACCTCGGAAATTGCCATCCCATTGGGATGCTGATCGGAACTCCAG CCTGTGACCTGCACCTGACAGGAATGTGGGATACCCTGATTGAGCGGGAGAATGCTATCGC ATATTGTTACCCCGGGGCTACCGTAAACGTCGAAGCCCTTAGGCAGAAGATAATGGAAAGC GGTGGCATCAATAAGATTTCGACAGGCTTCACTTATGGAAGTAGTATTAATAGCGCAGGAA CCACTCGAGCCTGTATGAGAAACGGCGGTAACAGCTTTTATGCTGAGCTCAAGTGGCTTGT CTCCAAGTCTAAGGGACAGAATTTCCCACAGACTACAAACACTTACAGGAATACCGATACA GCTGAGCATCTAATTATGTGGGGAATACATCACCCTTCTTCCACCCAGGAAAAAAACGACC TCTACGGCACTCAATCTCTCAGCATATCGGTGGGGAGTTCGACTTACCGAAACAACTTTGT CCCGGTTGTCGGTGCCAGGCCCCAGGTGAACGGACAAAGCGGTCGGATCGATTTTCATTGG ACTTTGGTCCAGCCTGGGGACAATATCACATTCTCACATAACGGCGGATTAATTGCCCCCT CTCGCGTGTCAAAGCTCATAGGCCGGGGCCTGGGGATTCAGTCTGACGCTCCAATTGATAA TAATTGCGAGTCAAAATGCTTCTGGCGCGGGGGGTCTATTAATACTCGATTGCCATTCCAG AATCTCAGTCCCCGGACCGTGGGGCAGTGCCCAAAGTATGTGAACCGGCGGAGCCTGATGC TGGCTACTGGAATGCGGAATGTGCCCGAACTTATTCAGGGCCGAGGTCTGTTCGGCGCCAT CGCCGGGTTCCTGGAGAATGGGTGGGAGGGCATGGTCGATGGATGGTATGGATTTCGTCAC CAGAACGCACAGGGCACAGGACAGGCTGCCGACTATAAGTCTACACAAGCGGCTATCGACC AGATTACTGGTAAACTCAACCGGCTGGTGGAGAAGACCAACACTGAGTTCGAATCCATTGA ATCTGAATTTTCGGAGATCGAACACCAGATTGGAAACGTGATCAACTGGACCAAGGACTCA ATCACTGACATCTGGACTTACCAGGCCGAACTGCTTGTGGCTATGGAGAATCAGCATACTA TCGATATGGCCGACTCCGAAATGCTCAACCTTTACGAGCGAGTGCGGAAACAATTGAGACA AAACGCCGAAGAGGATGGGAAGGGCTGTTTTGAAATATACCACGCCTGCGATGATAGTTGT ATGGAGTCAATCAGGAATAACACTTATGATCATAGTCAGTATAGAGAGGAAGCTCTTCTGA ATCGACTGAACATCAACCCAGTAACACTTAGTAGTGGGTACAAAGACATCATCTTGTGGTT CTCATTCGGAGCCTCTTGTTTTGTGCTGCTTGCCGTCGTAATGGGACTGTTTTTTTTTTGT CTCAAGAACGGCAACATGAGGTGCACTATTTGCATT 800 ATGTACAAAATCGTGGTGATCATCGCACTGCTAGGGGCAGTGAAAGGCCTGGATAAAATCT GCCTGGGACACCACGCAGTAGCCAACGGTACCATTGTGAAAACACTGACAAACGAACAGGA GGAGGTCACAAATGCTACAGAGACCGTGGAGTCTACAGGTATTAATCGGCTGTGCATGAAG GGAAGAAAGCACAAGGATCTGGGGAACTGCCACCCCATTGGAATGCTCATCGGGACACCTG CATGCGATCTGCACCTCACTGGCATGTGGGACACATTGATCGAAAGAGAAAATGCCATTGC ATATTGCTATCCTGGAGCAACGGTCAATGTGGAAGCACTGAGGCAAAAGATCATGGAGTCC GGAGGCATCAACAAAATCTCAACCGGTTTCACATACGGAAGCAGTATTAACTCTGCCGGCA CAACCCGTGCTTGCATGCGAAATGGAGGGAACTCTTTCTACGCGGAACTCAAATGGTTGGT GTCTAAGTCGAAAGGACAGAACTTTCCGCAAACTACAAATACTTACAGGAATACTGACACT GCAGAACATCTGATCATGTGGGGCATCCACCACCCCTCTTCAACACAGGAAAAGAATGACC TGTACGGGACCCAGAGTCTGTCAATCTCCGTGGGCTCCTCAACTTATCGTAACAACTTTGT CCCTGTTGTGGGAGCACGACCTCAAGTGAACGGACAGAGCGGGAGAATCGATTTTCACTGG ACCCTCGTGCAGCCTGGAGATAACATCACATTTAGCCATAACGGAGGGTTGATCGCTCCGT CCCGTGTGTCTAAACTTATCGGACGGGGCCTGGGTATCCAGAGTGATGCACCAATCGATAA CAACTGTGAGAGCAAGTGTTTCTGGCGTGGTGGTTCTATAAACACACGACTGCCCTTCCAG AACCTGTCGCCTAGAACCGTGGGACAGTGTCCTAAATACGTCAACCGAAGAAGCCTAATGC TGGCCACAGGAATGCGCAACGTGCCCGAGCTAATTCAGGGCAGGGGCCTCTTCGGCGCAAT CGCAGGCTTTCTGGAGAATGGGTGGGAGGGGATGGTGGATGGTTGGTACGGGTTCCGACAT CAGAACGCCCAGGGGACGGGGCAGGCAGCCGACTACAAATCCACTCAGGCCGCAATAGACC AGATTACCGGGAAACTGAATAGACTGGTGGAGAAAACAAATACTGAGTTCGAGAGTATTGA ATCAGAGTTCTCCGAAATCGAGCATCAGATCGGCAACGTGATTAACTGGACTAAGGACTCT ATCACAGATATATGGACATATCAGGCCGAGCTGCTGGTGGCCATGGAGAACCAGCACACCA TCGACATGGCCGACTCAGAAATGTTAAACCTCTATGAGCGGGTTCGTAAGCAGTTACGCCA AAACGCCGAAGAGGATGGCAAGGGGTGCTTCGAAATTTATCACGCTTGTGATGATTCCTGT ATGGAGTCCATTCGGAACAACACCTACGACCACAGCCAGTACCGCGAGGAGGCCCTTCTGA ATCGTCTGAACATAAACCCGGTCACCCTCAGTTCAGGATACAAGGACATAATTCTTTGGTT CTCCTTTGGCGCCTCATGCTTCGTGCTCCTGGCCGTGGTGATGGGGCTCTTTTTCTTCTGC TTGAAGAACGGGAACATGCGGTGTACTATCTGCATT 801 ATGTACAAAGTGGTGGTGATCATCGCCTTACTCGGGGCAGTGCGAGGGCTGGATAAGATTT GCCTGGGTCACCACGCTGTGGCAAACGGGACAACAGTGAAAACTCTCACAAATGAACAGGA GGAAGTCACCAACGCAACAGAGACCGTCGAAAGTACCTCACTCAATAAGTTGTGTATGAAA GGTCGCCGGTACAAGGACCTCGGGAACTGCCACCCAATTGGAATGCTGATTGGTACGCCCG TGTGTGACCTGCACCTGACCGGGACGTGGGACACCCTGATCGAGCGCGAGAATGCAACTGC TTACTGCTACCCCGGCGTGACCATTAACGAAGAAGCGCTGCGCCAGAAAATCATGGAATCA GGGGGGATTAGCAAAATGAGGACAGGGTTCACATATGGTCCTAGCATCAATAGCGCCGGAA CGACACGGAGCTGCATGCGCAACGGAGGCAACTCATTTTATGCCGAACTTAAGTGGCTGGT GTCTGGGACAAAGGGGCAGAACTTCCCACAGACTACTAATACATATCGAAATACCGACACT GCCGAGCACCTTATCATCTGGGGAATCCACCATCCTAGCTCAACTCAGGAAAAGAATGACC TCTACGGTACTCAGTCTCTGTCCATTAGCGTGGGATCCAGCACCTACCAAAACAATTTTGT TCCTGTTATCGGGGCAAGACCCCAAGTGAATGGCCAATCTGGGAGAATCGAATTCCACTGG ACACTGGTCAGACCAGGCGACAACATAACTTTTTCACACAATGGAGGACTTATCGCCCCAG ACAGGGTGTCAAAGCTGATCGGAAAGGGCATCGGAATTCAGAGTGGTGCGGTGATTGATAA GGATTGTGAAAGCAAGTGCTTTTGGCGCGGGGGCTCCATTATCACCGAGCTCCCTTTTCAA AACCTTAGCCCCCGGACAGTCGGCCAATGCCCAAAATATGTCAAAAAGCGCTCACTGCTCC TTGCCACGGGGATGCGGAACGTGCCGGAAGTGGTGCAAGGTCGAGGCCTCTTTGGCGCGAT CGCCGGATTCATCGAGAATGGTTGGGAAGGCATGGTGGACGGGTGGTACGGGTTTAGACAC CAGAATGCGCAGGGCATTGGGCAGGCTGCTGACTACAAATCAACTCAGACTGCGATTGATC AGATCACGGGAAAACTGAACCGTCTCATCGAAAAAACAAACACTGAGTTCGAATCCATCGA GTCGGAATTTAGTGAAATCGAACACCAGATCGGCAACGTCATTAATTGGACGAAGGACTCT ATTACAGATATCTGGACCTATCAGGCTGAGCTCTTGGTAGCAATGGAAAACCAACACACTA TCGATATGGCCGATAGCGAGATGCTGAACCTGTATGAAAGGGTTAGAAAGCAGCTGAGACA GAACGCTGAAGAAGACGGTAAGGGCTGCTTTGAGATCTATCATACATGCGACAATTCATGT ATGGAGTCCATACGGAATAATACATATGACCATTCGCAGTACCGAGAGGAGGCCTTACTGA ACAGACTGAACATCAATCCTGTTAAGCTGTCAAGCGGTTACAAGGACATAATTCTCTGGTT CTCCTTTGGTGCCTCCTGTTTCGTACTTCTCGCCGTCATCATGGGGTTGGGCTTCTTTTGC CTGAAAAATGGCAACATGAGATGCACTATATGCATT 802 ATGTATAAGATAGTGGTAATAATTGCCCTCTTGGGGGCAGTGAAAGGACTCGATAAGATAT GCCTGGGACACCATGCCGTGGCTAACGGCACAATTGTGAAAACGCTAACAAACGAGCAGGA GGAAGTTACCAACGCTACCGAAACCGTTGAGAGTACCGGCATTAATAGACTTTGTATGAAG GGCCGAAAACACAAAGATCTCGGGAACTGTCATCCGATCGGCATGTTGATTGGAACACCTG CATGTGATCTCCATTTAACAGGCATGTGGGATACATTGATTGAGCGGGAGAACGCTATAGC CTATTGCTATCCCGGAGCCACAGTGAATGTTGAGGCGCTTCGTCAGAAAATCATGGAGAGC GGAGGCATCAACAAGATCTCCACCGGGTTTACCTATGGCTCGTCTATAAACTCAGCTGGTA CAACCAGGGCTTGCATGAGAAATGGGGGAAATTCCTTTTATGCAGAGCTGAAGTGGCTGGT GTCAAAGAGCAAAGGACAGAATTTCCCGCAGACCACAAACACCTATCGTAATACCGACACC GCCGAGCACCTTATTATGTGGGGCATACACCATCCAAGCTCAACCCAGGAGAAGAACGATC TGTACGGCACGCAGAGTCTGAGCATCTCAGTCGGCTCTTCCACTTATAGGAACAACTTCGT TCCAGTTGTCGGGGCGCGCCCTCAAGTCAACGGACAATCTGGCAGGATCGACTTCCACTGG ACTCTTGTACAACCCGGCGATAACATCACCTTCTCCCATAACGGGGGTCTTATCGCCCCAT CCCGGGTGAGCAAGCTCATTGGTCGCGGACTGGGGATTCAGAGCGATGCGCCTATTGACAA TAACTGCGAGAGTAAATGCTTTTGGAGGGGCGGTAGCATCAACACCCGGTTGCCTTTCCAA AACCTTTCCCCTAGAACAGTTGGCCAGTGTCCGAAGTATGTAAACAGGCGAAGTCTCATGC TCGCGACAGGCATGCGGAATGTTCCCGAGCTGATTCAGGGCAGGGGACTGTTTGGAGCTAT CGCGGGATTTCTGGAAAACGGTTGGGAAGGGATGGTGGACGGATGGTATGGATTCCGCCAC CAGAATGCACAAGGAACGGGCCAGGCCGCCGACTACAAGTCCACTCAGGCCGCTATTGATC AGATTACCGGCAAGCTCAATCGCCTGGTGGAGAAGACTAATACCGAGTTCGAGAGCATCGA GTCCGAATTCTCGGAAATTGAGCATCAGATCGGCAATGTCATAAATTGGACCAAAGACTCA ATCACAGATATATGGACTTATCAGGCTGAGTTGCTTGTGGCTATGGAAAACCAGCACACAA TCGATATGGCTGATTCCGAGATGCTTAATCTGTATGAACGCGTAAGGAAGCAGTTACGGCA AAATGCAGAAGAAGATGGCAAGGGCTGTTTTGAGATCTATCATGCCTGCGATGACAGTTGC ATGGAGTCAATTAGGAATAATACGTATGATCACTCTCAGTATCGTGAGGAAGCTCTGCTGA ACCGTCTGAACATCAATCCTGTGACCTTATCGTCCGGATATAAGGATATCATTCTATGGTT CAGCTTTGGCGCTAGCTGCTTTGTCTTACTCGCTGTGGTCATGGGCCTGTTTTTTTTCTGC TTAAAGAACGGGAACATGCGTTGTACAATCTGCATT 803 ATGTATAAAATCGTCGTTATAATCGCGTTATTGGGAGCAGTGAAGGGCTTAGACAAGATTT GTCTGGGACATCATGCAGTGGTGAACGGAACCATCGTGAAGACACTAACAAATGAACAGGA GGAAGTCACCAACGCAACCGAAACTGTGGAATCTACAGGTCTAAACAGGTTGTGTATGAAA GGCAGGAATCATAAAGACCTCGGCAACTGCCATCCAATTGGTATGCTTATTGGAACGCCCG CATGTGACCTGCATCTCACAGGTACATGGGACACACTCATTGAGCGCGAAAATGCTATCGC CTACTGCTATCCTGGCGCTACCGTCAATGAGGAGGCACTGAGACAGAAGATCATGGAGAGC GGCGGAATAAACAAAATTTCTACAGGCTTCACCTATGGGAGCAGCATCAATTCTGCCGGCA CAACAAGGGCCTGTATGCGTAACGGGGGAAACTCCTTTTACGCCGAGCTGAAATGGTTGGT GTCCAAGAGCAAGGGGCAGAACTTTCCCCAGACCACAAATACATATAGGAATACGGATACT GCCGAGCACCTCATCATGTGGGGCATCCATCACCCAAGCTCCACCCAGGAGAAGAATGACC TCTACGGGACCCAGTCCCTTAGCATTTCTGTGGGCAGTAGCACTTATCAAAATAACTTCGT CCCCGTCGTAGGGGCGAGACCACAGGTTAACGGACAAAGCGGCAGAATTGACTTCCACTGG ACACTCGTTCAGCCAGGTGATAATATTACTTTTAGCCATAATGGGGGACTGATAGCACCCA GCAGAGTGAGTAAGTTGATAGGCAGGGGGCTTGGTATTCAGTCAGATGCGCCCATTGATAA CAACTGTGAGAGTAAGTGCTTCTGGAGAGGGGGCTCCATTAATACCCGCTTGCCATTTCAA AACCTGTCCCCCAGGACTGTAGGGCAGTGCCCTAAGTACGTGAACAAACGGTCCTTAATGC TGGCCACTGGTATGCGCAATGTGCCAGAGCTCATGCAGGGCAGAGGGCTCTTTGGAGCCAT AGCAGGGTTTATTGAAAATGGGTGGGAGGGCATGGTGGACGGATGGTACGGATTTAGACAC CAAAACGCGCAGGGCACTGGACAGGCGGCCGACTATAAGTCCACCCAGGCCGCGATCGATC AGATCACCGGAAAGTTGAACCGCTTAATAGAGAAGACAAACACCGAGTTCGAAAGCATAGA GTCCGAATTTTCCGAAATCGAACACCAGATCGGCAACGTGATCAACTGGACGAAGGATTCG ATTACCGACATTTGGACTTATCAGGCTGAACTACTCGTGGCTATGGAGAACCAACATACTA TCGATATGGCAGATTCTGAAATGCTTAACCTCTATGAACGGGTTAGGAAACAGCTGAGGCA GAACGCAGAAGAAGACGGCAAGGGGTGCTTCGAAATTTATCATGCATGTGACGATAGTTGC ATGGAAAGCATTAGAAACAACACCTATGACCATTCTCAGTATCGGGAGGAGGCACTCCTGA ATCGTCTGAATATCAACCCAGTCACACTGAGTTCAGGGTATAAAGACATAATTCTCTGGTT CTCATTCGGAGCCTCCTGTTTTGTGCTACTCGCAGTTGTGATGGGACTGGTCTTTTTTTGC CTGAAAAATGGCAATATGAGATGTACAATTTGCATC 804 ATGTATAAAATTGTGGTCATAATTGCACTGCTCGGCGCAGTAAAGGGGCTCGATAAGATTT GCCTGGGCCACCACGCCGTCGCTAACGGGACGATTGTCAAGACCCTGACTAACGAACAAGA GGAGGTGACTAATGCTACCGAAACCGTCGAATCCACCGGCATTAACAGACTCTGTATGAAA GGCAGAAAACATAAGGATCTGGGAAATTGCCACCCAATCGGAATGCTGATCGGGACACCCG CCTGCGACCTGCACCTGACTGGGACTTGGGATACACTTATCGAAAGGGAGAATGCCATTGC TTATTGTTACCCCGGCGCAACAGCGAATGTTGAAGCCCTGCGGCAAAAAATTATGGAATCC GGTGGCATTGACAAGATCAGCACCGGGTTCACCTACGGCTCATCTATTAACAGTGCTGGGA CCACCAGAGCTTGCATGCGGAACGGTGGCAACAGTTTCTACGCTGAACTCAAGTGGTTAGT CTCAAAGTCTAAAGGACAGAACTTCCCCCAGACTACTAATACGTATAGGAACACTGATACT GCTGAACATCTGATTATGTGGGGCATTCACCATCCAAGCTCAATTCAGGAGAAAAACGACC TGTATGGCACCCAGTCGCTGTCTATCAGCGTGGGTTCCAGCACCTACCGGAACAATTTTGT ACCGGTGGTTGGCGCGCGTCCTCAGGTCAATGGTCAATCTGGGCGGATTGACTTCCACTGG ACTCTGGTTCAACCCGGCGACAACATAACTTTCTCTCACAATGGTGGATTGATCGCTCCTT CCCGCGTTTCAAAACTGATAGGCCGCGGCTTAGGAATTCAGAGCGACGCCCCGATAGACAA TAATTGCGAGTCCAAGTGCTTCTGGAGGGGAGGAAGCATTAACACGCGGTTGCCTTTCCAG AACCTGTCCCCAAGGACAGTGGGACAATGCCCAAAATATGTCAATAGAAGAAGTCTCATGC TGGCGACTGGTATGCGCAACGTGCCTGAGCTTATCCAGGGCCGCGGATTGTTCGGGGCAAT CGCCGGCTTCCTGGAAAATGGGTGGGAAGGAATGGTGGATGGTTGGTACGGTTTTCGACAT CAGAATGCCCAGGGTACTGGCCAGGCTGCAGACTATAAAAGCACTCAGGCTGCCATTGACC AGATCACGGGTAAACTGAATAGGCTGGTGGAGAAGACGAACACAGAGTTCGAGTCTATTGA ATCTGAGTTTTCTGAGATAGAGCACCAGATCGGAAACGTCATCAACTGGACCATGGATTCC ATAACTGACATCTGGACTTACCAGGCGGAACTGCTGGTTGCAATGGAGAATCAGCACACTA TTGACATGGCCGATTCCGAGATGCTCAATCTTTACGAGCGGGTCCGTAAACAGCTAAGGCA GAATGCCGAGGAAGATGGGAAGGGTTGCTTCGAAATATATCATGCATGTGATGATTCTTGT ATGGAGTCGATTCGTAATAACACCTACGATCACAGTCAATACAGAGAAGAAGCTCTTCTTA ATCGGCTAAACATTAACCCAGTCACATTGAGCTCAGGATACAAGGACATCATCCTGTGGTT CTCATTCGGGGCTTCCTGTTTTGTCCTGCTGGCCGTGGTCATGGGGCTGGTTTTTTTTTGC CTGAAGAACGGCAATATGAGATGCACAATTTGCATC 805 ATGTATAAGGTGGTTGTGATTATTGCGCTGCTCGGGGCCGTTCGAGGCCTGGATAAAATCT GTCTGGGCCATCACGCTGTCGCCAATGGCACGACTGTGAAAACTTTAACAAATGAGCAGGA AGAGGTGACAAATGCCACTGAAACCGTCGAGAGTACATCACTGAATAAACTGTGCATGAAG GGACGCCGCTATAAGGACCTGGGTAATTGCCATCCAATTGGTATGTTGATCGGGACCCCTG TGTGCGACTTACACCTAACTGGCACTTGGGACACACTGATCGAGAGGGAGAATGCCACCGC CTATTGTTACCCTGGTGTGACCATTAACGAAGAGGCTCTCAGACAAAAGATTATGGAGTCT GGAGGAATCTCTAAGATGCGTACTGGGTTTACCTATGGGCCAAGCATCAACTCGGCTGGCA CTACTCGCTCCTGTATGAGAAATGGAGGAAACTCCTTTTATGCTGAGTTGAAGTGGCTCGT TTCCGGCACCAAGGGGCAAAACTTTCCACAGACGACCAATACTTATAGGAATACGGACACC GCTGAACACCTGATTATTTGGGGAATCCATCACCCCAGCTCTACGCAGGAGAAGAACGACC TTTACGGTACCCAGAGTCTTTCGATTAGCGTGGGCAGCAGCACATACCAGAATAATTTCGT GCCCGTAATAGGTGCACGGCCTCAGGTGAATGGACAGTCGGGCCGGATAGAATTCCACTGG ACGCTCGTTAGGCCCGGAGACAACATAACTTTTTCTCATAATGGCGGACTTATCGCTCCAG ATCGGGTCAGCAAGCTTATAGGGAAGGGGATCGGCATCCAGTCCGGTGCTGTCATCGATAA GGACTGTGAATCCAAGTGTTTCTGGCGTGGCGGTTCAATTATCACCGAACTACCTTTTCAA AACTTGTCACCAAGAACCGTGGGACAGTGTCCAAAGTATGTCAAAAAAAGATCCTTGTTAC TGGCTACCGGGATGAGGAATGTGCCTGAAGTCGTTCAGGGCCGCGGGCTGTTCGGAGCCAT CGCGGGATTTATCGAAAACGGGTGGGAGGGGATGGTGGACGGTTGGTACGGATTCAGGCAT CAGAATGCTCAGGGGATTGGGCAGGCTGCCGACTACAAGTCTACCCAGACGGCTATTGACC AGATCACCGGCAAGTTGAATCGCCTGATAGAAAAAACTAATACGGAATTCGAAAGCATCGA ATCCGAGTTCTCAGAAATCGAGCACCAGATAGGTAATGTAATCAATTGGACAAAGGACTCT ATCACCGATATCTGGACCTATCAGGCAGAATTGCTGGTGGCAATGGAGAACCAGCACACAA TCGATATGGCTGATTCAGAAATGCTGAATTTGTACGAGAGGGTCCGGAAGCAGCTCCGACA GAACGCAGAAGAAGATGGGAAGGGTTGTTTCGAGATATATCATACCTGCGACAACTCGTGT ATGGAATCAATACGCAATAATACATACGATCACAGTCAGTATCGTGAGGAGGCTCTCCTGA ACAGGCTGAATATTAATCCTGTGAAACTGAGCTCCGGGTACAAGGATATTATTCTGTGGTT CAGTTTTGGCGCTTCATGTTTCGTGTTGCTGGCAGTTATTATGGGGCTTGGTTTCTTCTGC CTGAAGAATGGGAACATGCGCTGCACGATTTGCATA 806 ATGTATAAGGTGGTCGTAATCATCGCCCTTCTGGGTGCTGTCCGGGGCTTGGACAAAATTT GTCTCGGGCATCACGCAGTGGCTAACGGCACAATAGTGAAGACCCTCACTAACGAACAGGA GGAAGTGACAAACGCGACAGAAACAGTTGAGAGTAAATCCCTCGGCAAGCTGTGCATGAAA GGGAGGAGTTATAATGACCTCGGCAATTGTCATCCGATAGGTATTCTGATCGGCACTCCTG CGTGCGACCTGCACCTGACCGGGACCTGGGATACCCTCATCGAGAGGGAGAACGCCGTGGC CTACTGCTACCCAGGCGCCACAGTAAATGAGGAAGCGCTGCGGCAGAAAATTATGGAATCT GGAGGAATTAGCAAGATTTCTACTGGCTTCACCTATGGGACAAGCATCAACAGCGCCGGTA CCACGAAGGCCTGTATGAGAAACGGTGGGAATTCTTTTTACGCAGAGCTCAAATGGCTGGT GAGCAAAAACAAGGGGCAAAATTTCCCCCAGACCACAAACACATATAGGAATACAGACACA GCTGAGCATTTAATTATTTGGGGCATCCATCACCCCTCCAGCACACAAGAAAAGAATGACC TGTACGGTACCCAGTCTCTCTCTATTAGCGTTGGCTCTTCTACATACCAGAATAACTTTGT TCCAGTCGTCGGAGCACGGCCACAGGTTAACGGGCAGAGTGGACGTATCGATTTCCACTGG ACTCTTCTACAGCCTGGCGACAATATTACTTTTAGTCACAACGGCGGCCTTATAGCCCCGT CCAGAGTCTCCAAGCTGATCGGCAGAGGGCTGGGCATTCAGTCCGAGGCTCCAATTGATAA TGGCTGCGAAAGCAAATGCTTTTGGAAAGGCGGGAGTATCAACACAAAACTGCCCTTTCAG AATCTGAGCCCTCGAACTGTGGGTCAGTGCCCAAAATACGTTAATAAGCGGAGTCTGATGT TAGCTACTGGCATGCGGAACGTTCCAGAAATCATGCACGGCCGCGGACTCTTTGGAGCTAT CGCCGGGTTTATAGAAAATGGCTGGGAAGGCATGGTTGACGGCTGGTACGGATTCAGGCAC CAAAACGCCCAGGGAACCGGACAGGCCGCCGATTACAAAAGCACGCAAGCAGCTATTGATC AGATCACTGGAAAACTCAATCGACTGATCGAAAAGACTAACACAGAATTTGAATCCATTGA GTCCGAATTTAGTGAGATCGAGCACCAAATCGGCAACATCATTAACTGGACGAAGGACAGC ATAACAGACATATGGACATATCAGGCAGAGCTCCTGGTCGCAATGGAAAACCAGCATACCA TAGATATGGCTGATTCTGAGATGCTCAATCTGTATGAACGAGTCAGAAAGCAATTAAGACA AAACGCTGAGGAGGATGGTAAGGGATGCTTCGAGATTTACCATGCTTGCGACGATTCCTGC ATGGAAAGCATCCGTAATAACACCTACGACCACAGCCAATACCGTGAAGAAGCCCTCCTAA ATCGATTGAACATTAATCCTGTGAAATTGAGTTCCGGCTACAAGGACATCATCCTGTGGTT CTCATTTGGCGCATCATGCTTGATTCTTTTGGCCGTGGTGATGGGCCTGGTTTTCTTCTGT CTGAAAAATGGCAACATGAGATGTACTATCTGCATT 807 ATGTACAAGATCGTGGTTATAATTGCCCTCCTGGGCGCCGTTAAGGGCCTTGATAAGATAT GTCTGGGGCACCATGCCGTGGCTAATGGGACCATAGTGAAAACCCTGACTAATGAGCAGGA GGAGGTCACTAACGCCACCGAGACTGTGGAATCCACCGGCATCAACAGGCTGTGTATGAAG GGGCGCAAACACAAGGACCTAGGGAATTGCCACCCCATCGGTATGCTTATCGGCACGCCAG CCTGTGACCTTCACCTGACTGGGATGTGGGACACTCTGATTGAAAGAGAAAACGCTATAGC GTACTGCTACCCCGGCGCAACTGTGAACGTAGAAGCGTTGCGGCAGAAGATCATGGAGTCT GGGGGAATCAATAAGATCTCAACAGGGTTTACATACGGCTCATCTATCAATTCCGCGGGCA CGACCAGGGCGTGCATGAGGAACGGCGGGAACTCTTTTTACGCCGAGCTTAAATGGTTAGT ATCTAAGAGCAAGGGGCAGAACTTTCCACAAACGACCAACACATACCGCAACACCGATACC GCAGAACACCTCATCATGTGGGGAATCCACCATCCCAGTTCCACTCAAGAAAAAAACGATC TATACGGCACTCAGTCCCTCTCAATCTCCGTGGGAAGTAGCACATATCGGAACAACTTCGT GCCCGTGGTTGGGGCCCGCCCCCAGGTCAATGGCCAGTCAGGAAGAATTGACTTCCATTGG ACACTTGTGCAGCCAGGCGACAATATCACATTTTCCCACAACGGCGGATTGATCGCCCCCT CCAGAGTTAGCAAGCTGATCGGGAGAGGCCTGGGTATCCAGAGTGACGCGCCAATCGATAA CAACTGCGAGAGCAAGTGCTTTTGGCGCGGAGGCTCAATTAACACACGGCTACCTTTCCAA AACCTCAGTCCGCGTACAGTTGGCCAGTGCCCCAAGTATGTGAACCGGAGATCTTTGATGC TCGCTACCGGCATGCGAAATGTCCCGGAGCTGATTCAAGGCCGCGGGCTCTTTGGAGCGAT TGCGGGGTTTCTGGAGAACGGATGGGAAGGAATGGTGGATGGTTGGTACGGATTTCGGCAT CAAAATGCACAGGGGACTGGCCAAGCCGCAGACTATAAGAGCACCCAGGCTGCGATCGACC AGATCACCGGAAAGCTCAACCGCCTGGTGGAGAAGACCAATACGGAATTTGAATCAATCGA AAGCGAGTTTAGTGAAATAGAACACCAGATTGGTAATGTGATTAATTGGACAAAAGACAGC ATTACTGATATTTGGACATATCAGGCTGAGTTACTGGTAGCTATGGAGAATCAGCACACCA TTGATATGGCCGACTCCGAAATGCTGAATCTGTACGAACGGGTTCGGAAACAGCTCAGGCA GAACGCCGAAGAAGACGGTAAGGGATGCTTCGAAATCTACCACGCCTGCGATGATAGTTGC ATGGAGTCTATACGGAACAACACCTATGACCATTCTCAGTATAGAGAAGAGGCCCTACTGA ACCGTTTGAACATTAATCCAGTGACCCTGTCCTCCGGTTACAAGGACATAATCCTGTGGTT CTCGTTTGGTGCTAGCTGCTTTGTGCTGCTGGCGGTGGTAATGGGACTGTTTTTCTTTTGC CTGAAAAATGGCAATATGAGATGCACCATTTGCATC 808 ATGTACAAGATTGTGGTGATTATAGCCCTTCTGGGGGCTGTCAAGGGACTGGACAAAATCT GCCTGGGACATCATGCTGTGGCAAACGGAACTATTGTGAAGACTTTGACTAACGAACAGGA GGAGGTGACCAACGCCACCGAAACCGTGGAATCCACAGGCATCAACCGGCTCTGCATGAAA GGAAGAAAGCACAAGGACCTGGGCAATTGTCATCCAATCGGAATGCTTATCGGGACTCCGG CCTGTGATTTGCATCTGACCGGCATGTGGGATACGTTAATCGAACGAGAGAACGCCATTGC CTATTGCTACCCTGGCGCGACCGTGAATGTCGAGGCCTTGAGGCAGAAGATCATGGAGAGC GGCGGAATCAACAAAATAAGCACTGGTTTCACCTACGGTAGTAGCATAAATTCCGCTGGGA CCACGCGGGCCTGCATGCGGAACGGCGGCAATTCCTTTTACGCAGAGCTTAAATGGTTAGT GAGCAAAAGCAAGGGACAGAATTTCCCCCAGACCACAAACACATATCGTAACACCGACACC GCGGAACATCTGATTATGTGGGGCATACATCACCCCTCTTCCACGCAAGAAAAGAATGACC TGTACGGAACACAATCCTTATCCATTAGCGTAGGAAGCAGCACTTATCGGAACAACTTTGT GCCCGTGGTGGGAGCTCGGCCTCAGGTAAACGGCCAGTCCGGTCGGATAGATTTCCATTGG ACTTTGGTTCAGCCGGGGGATAACATTACATTTTCCCATAACGGCGGCCTCATTGCTCCCT CGCGGGTCTCTAAACTTATTGGGCGGGGCCTGGGGATCCAGTCAGATGCCCCTATCGATAA TAATTGCGAATCCAAATGTTTTTGGAGAGGAGGCAGTATTAACACCCGGCTGCCTTTCCAG AATCTCAGCCCCCGTACAGTCGGACAGTGTCCCAAATATGTGAATAGACGCTCGCTAATGC TGGCCACCGGCATGCGGAACGTTCCTGAGCTGATCCAGGGACGGGGGCTCTTTGGTGCAAT TGCTGGATTTCTGGAAAATGGCTGGGAAGGCATGGTGGATGGCTGGTACGGCTTTAGGCAC CAGAATGCCCAAGGCACGGGGCAGGCAGCCGACTACAAATCCACACAAGCCGCCATTGACC AAATCACCGGGAAATTAAATAGGCTTGTGGAGAAAACCAATACCGAATTCGAAAGCATCGA GAGCGAATTTTCAGAGATCGAGCACCAGATCGGGAATGTGATAAATTGGACCAAAGATTCC ATTACCGATATTTGGACTTACCAAGCTGAGCTGCTCGTGGCCATGGAAAACCAGCACACAA TCGATATGGCCGACTCTGAAATGTTGAACTTGTATGAAAGAGTGCGAAAACAGTTGCGTCA AAACGCCGAGGAAGACGGGAAAGGTTGTTTCGAAATCTATCACGCGTGCGATGACAGCTGT ATGGAAAGTATTAGGAACAATACATATGACCACTCACAGTATCGCGAGGAGGCACTGTTGA ATCGCCTAAACATCAACCCCGTTACATTGTCTTCTGGTTACAAAGACATTATCTTATGGTT TTCGTTTGGAGCCTCGTGTTTCGTGCTCCTAGCGGTAGTGATGGGGCTCTTCTTCTTCTGT CTGAAGAACGGGAACATGCGCTGCACTATCTGTATC 809 ATGTACAAGATCGTAGTCATCATCGCCCTGCTGGGGGCCGTCAAAGGACTGGACAAGATTT GCCTGGGCCATCATGCAGTCGCAAATGGCACTATCGTGAAGACTCTGACAAACGAACAGGA AGAGGTGACAAATGCCACTGAAACAGTCGAGTCTACTGGGATCAACAGACTTTGCATGAAG GGCCGCAAGCACAAGGACCTGGGTAATTGCCACCCCATTGGAATGCTTATTGGCACACCCG CTTGCGACTTACACCTAACCGGTATGTGGGATACTCTGATCGAAAGGGAAAACGCCATTGC ATACTGCTACCCCGGCGCTACAGTGAACGTCGAGGCTCTGCGCCAGAAAATTATGGAGTCT GGTGGAATCAATAAGATCTCAACTGGCTTCACCTATGGGAGTTCCATCAACAGCGCTGGGA CTACGCGTGCGTGCATGCGTAACGGCGGAAACAGCTTTTACGCAGAGCTGAAATGGCTCGT CAGCAAGTCCAAGGGTCAGAATTTCCCACAGACTACGAATACCTACCGAAATACTGACACT GCGGAGCATCTCATCATGTGGGGAATCCACCATCCAAGCAGCACCCAGGAAAAGAACGATC TGTACGGCACTCAGTCCCTAAGCATCTCCGTCGGCAGCAGTACTTATCGCAATAACTTTGT CCCCGTGGTAGGAGCCCGTCCTCAGGTGAACGGACAGAGCGGACGTATCGACTTTCATTGG ACACTCGTGCAACCCGGGGACAATATAACGTTCAGCCATAACGGAGGTTTAATAGCGCCTA GCCGTGTGTCCAAACTCATCGGCCGTGGCCTGGGGATCCAATCCGATGCACCAATCGACAA TAACTGCGAGTCTAAGTGCTTCTGGCGGGGAGGCTCAATTAATACCCGCCTACCCTTCCAG AATCTGTCACCCAGGACCGTGGGCCAGTGTCCTAAGTACGTCAACAGGCGATCTCTCATGT TGGCCACTGGCATGCGAAACGTGCCTGAGCTGATCCAAGGTAGAGGGCTGTTCGGAGCAAT CGCCGGATTCCTGGAGAACGGCTGGGAGGGAATGGTGGACGGATGGTATGGTTTCAGGCAC CAAAACGCTCAAGGAACTGGCCAGGCAGCTGACTATAAGTCCACTCAGGCTGCAATCGATC AAATCACCGGCAAGCTGAACAGGCTCGTTGAGAAAACGAACACGGAATTTGAGTCCATCGA ATCTGAATTTTCCGAGATCGAACATCAGATAGGCAACGTTATCAACTGGACGAAGGACTCT ATCACTGACATTTGGACGTATCAGGCGGAGCTCTTAGTGGCCATGGAAAACCAGCACACTA TCGACATGGCCGACAGTGAAATGCTGAACCTCTACGAAAGAGTTCGCAAGCAGCTCCGGCA GAATGCAGAAGAGGATGGAAAAGGCTGTTTTGAAATCTACCACGCATGTGACGACTCATGC ATGGAGTCTATACGAAATAATACTTACGACCATTCGCAATATCGCGAGGAGGCTCTGCTAA ATAGGTTGAACATCAATCCCGTCACACTGTCCAGTGGCTACAAGGATATCATTCTGTGGTT CTCATTTGGAGCCTCCTGCTTCGTTCTGCTGGCCGTGGTTATGGGATTATTCTTCTTTTGC CTCAAGAACGGAAATATGCGCTGCACAATCTGCATC 810 ATGTACAAGATTGTGGTGATTATCGCATTGCTGGGCGCCGTGAAGGGGCTGGATAAAATAT GTCTGGGGCACCATGCCGTAGCAAACGGTACGATAGTTAAGACTCTTACCAACGAACAGGA AGAGGTGACGAACGCGACAGAGACCGTTGAGAGTACAGGTATTAATCGACTCTGTATGAAG GGCCGCAAGCACAAGGACCTGGGCAATTGCCACCCCATCGGGATGCTGATCGGCACTCCTG CGTGTGATCTGCACTTGACCGGCACTTGGGACACTTTGATTGAGAGAGAAAACGCGATTGC TTATTGCTACCCTGGAGCAACCGCCAATGTTGAAGCCCTGAGGCAGAAGATTATGGAGTCG GGAGGTATTGATAAGATCTCCACTGGATTCACTTACGGCTCATCTATAAATAGCGCCGGGA CTACCCGCGCTTGCATGAGGAACGGGGGGAACAGCTTCTATGCCGAGCTCAAATGGCTTGT GTCTAAGTCGAAAGGTCAAAACTTCCCACAGACAACTAACACATACCGCAACACCGACACT GCAGAGCACTTGATTATGTGGGGCATCCATCATCCGTCTAGCATCCAGGAGAAGAATGATC TCTATGGGACCCAGAGCCTCAGCATTTCAGTCGGAAGTTCCACCTACAGGAATAATTTCGT GCCTGTGGTGGGCGCACGGCCTCAAGTGAACGGCCAGTCCGGAAGAATAGACTTTCACTGG ACTCTGGTGCAGCCGGGGGATAACATTACATTCTCGCACAACGGTGGGCTTATAGCCCCCA GCAGAGTAAGTAAACTTATCGGTCGGGGTTTGGGCATTCAGTCGGATGCCCCTATCGATAA TAATTGTGAATCTAAATGTTTTTGGAGGGGCGGGAGCATCAACACCAGGCTGCCTTTCCAG AATCTGTCCCCCCGAACTGTGGGACAGTGCCCCAAGTATGTTAACAGACGGTCCCTTATGC TGGCCACTGGCATGCGCAACGTCCCCGAACTCATTCAGGGGCGCGGTCTGTTTGGTGCAAT TGCCGGGTTTCTGGAGAACGGCTGGGAAGGGATGGTAGACGGTTGGTATGGCTTCCGGCAC CAAAACGCCCAGGGAACTGGCCAAGCTGCCGACTACAAATCTACCCAGGCTGCCATAGATC AGATCACTGGCAAACTCAATCGCCTGGTGGAAAAAACCAACACAGAGTTTGAGAGCATCGA GTCCGAATTCTCCGAAATCGAACACCAGATCGGTAATGTGATTAACTGGACCATGGATAGT ATCACCGACATATGGACATATCAGGCTGAACTCCTGGTGGCCATGGAGAACCAACATACTA TTGATATGGCCGACTCAGAAATGTTAAATCTGTATGAGCGTGTGAGAAAACAGCTCAGGCA GAACGCTGAGGAAGACGGAAAGGGCTGCTTCGAAATCTACCACGCATGCGATGACTCTTGC ATGGAATCAATCCGGAACAACACATATGACCACAGCCAGTACCGGGAGGAGGCCCTTTTGA ATAGGCTGAATATCAATCCCGTCACGCTTTCTTCCGGTTACAAAGATATAATTCTGTGGTT CTCATTCGGGGCAAGCTGCTTTGTGCTTCTCGCTGTCGTGATGGGCCTCGTTTTCTTTTGC TTGAAGAATGGAAATATGCGGTGCACGATCTGTATC 811 ATGTACAAGATCATCGTTATAATCGCACTCCTGGGCGCCGTCAAAGGCCTGGACAAGATTT GCCTAGGGCATCACGCCGTAGCCAATGGAACCATTGTCAAGACCCTGACCAACGAGCAGGA AGAGGTGACAAACGCCACAGAGACAGTAGAGTCCACCGGAATCAATCGCTTGTGCATGAAA GGACGGAAGCATAAAGACTTAGGAAATTGTCATCCAATCGGCATGCTGATTGGGACACCCG CCTGTGACTTGCATTTGACAGGGACCTGGGACACCCTTATCGAGCGTGAGAATGCCATCGC GTACTGCTACCCCGGGGCTACGGTGAACGTCGAGGCTTTAAGACAGAAGATCATGGAGTCC GGCGGAATCGATAAGATTTCTACCGGTTTCACTTACGGGAGTTCTATCAACTCTGCAGGAA CCACTCGGGCCTGCATGAGGAATGGAGGCAACTCATTCTACGCAGAATTGAAATGGCTGGT AAGCAAGAGCAAGGGCCAAAATTTCCCCCAGACCACGAATACCTATAGGAATACTGACACT GCGGAGCATCTGATTATGTGGGGCATCCACCACCCGAGCTCAACTCAAGAGAAAAATGATC TTTACGGAACCCAGAGCCTGTCAATTTCCGTGGGGAGCAGTACTTATCGCAATAATTTCGT ACCTGTCGTAGGTGCCAGACCGCAGGTCAATGGACAGAGCGGCCGTATCGACTTCCACTGG ACACTGGTGCAGCCAGGGGATAACATCACTTTTTCCCACAACGGCGGCCTGATCGCTCCCA GCAGGGTGTCGAAGCTGATCGGTCGGGGGCTGGGGATACAGTCAGACGCACCCATTGATAA CAATTGCGAGAGCAAATGTTTCTGGCGTGGTGGAAGCATAAACACAAGACTTCCGTTTCAG AACCTTAGTCCACGCACTGTCGGCCAGTGCCCAAAATACGTAAACCGACGTTCCCTGATGC TCGCTACGGGGATGCGAAACGTACCAGAGTTAATCCAGGGCCGCGGGCTGTTCGGAGCTAT TGCCGGCTTCCTCGAAAACGGGTGGGAAGGCATGGTAGACGGGTGGTACGGGTTTAGGCAT CAAAACGCCCAGGGCACAGGCCAGGCGGCCGACTATAAAAGCACCCAGGCTGCAATTGACC AGATTACCGGGAAACTGAACAGACTTGTAGAAAAAACCAATACAGAATTTGAGTCTATCGA ATCAGAGTTCTCTGAGATAGAGCATCAGATCGGTAACGTGATCAATTGGACTAAAGATTCA ATAACTGACATATGGACTTACCAGGCCGAACTTCTGGTGGCTATGGAAAACCAGCATACAA TTGACATGGCCGACTCCGAGATGTTGAACCTTTACGAGCGCGTGCGTAAACAGCTGAGGCA AAATGCTGAAGAAGACGGAAAAGGCTGCTTCGAGATATATCACGCTTGTGACGATTCATGT ATGGAATCCATACGGAATAATACTTACGACCATTCGCAATATAGGGAGGAGGCCTTGTTGA ACCGGCTGAATATCAATCCAGTGACCCTTAGCTCCGGCTATAAAGATATTATTTTGTGGTT CTCTTTTGGAGCTTCCTGCTTTGTCCTATTAGCTGTGGTCATGGGCCTCTTTTTTTTCTGC CTTAAAAATGGGAATATGCGGTGCACTATCTGTATC 812 ATGTATAAGATCGTGGTGATAATCGCCCTGCTGGGGGCTGTTAAAGGTCTCGACAAAATCT GCTTAGGGCATCACGCCGTGGCCAATGGCACCATAGTTAAGACCCTGACCAATGAACAGGA AGAGGTTACCAACGCAACGGAGACCGTCGAATCTACCGGCATCAACCGATTATGCATGAAG GGTCGCAAGCACAAAGATCTCGGAAACTGCCACCCCATTGGCATGCTCATCGGGACCCCTG CTTGCGACCTGCATTTAACAGGTATGTGGGACACGCTGATTGAAAGAGAGAACGCGATCGC CTACTGTTACCCAGGCGCTACAGTGAACGTGGAGGCTCTGCGACAGAAAATTATGGAGTCG GGCGGCATCAATAAAATCAGCACGGGTTTCACTTATGGCAGTTCAATCAACTCCGCCGGTA CTACCAGGGCCTGTATGCGGAATGGGGGCAACTCTTTTTATGCCGAGCTGAAGTGGCTGGT CTCCAAGAGTAAGGGCCAGAATTTCCCACAGACCACAAACACTTACAGGAACACGGACACC GCCGAGCATCTGATTATGTGGGGCATTCACCACCCATCTAGTACCCAGGAGAAGAACGACT TGTACGGCACACAGTCTCTGTCAATTAGTGTTGGGTCTTCCACATATCGTAATAATTTTGT ACCGGTCGTGGGCGCGGGGCCCCAAGTGAACGGTCAAAGCGGTAGGATTGATTTTCATTGG ACCCTCGTGCAACCAGGAGATAATATCACTTTTTCGCACAATGGCGGTCTCATAGCCCCGA GCCGGGTCAGCAAGCTAATCGGACGGGGGCTCGGGATCCAGTCCGATGCTCCCATCGATAA TAACTGTGAATCTAAGTGTTTTTGGCGGGGCGGATCCATAAACACCAGGCTTCCCTTCCAG AACTTGTCCCCAAGGACGGTAGGCCAATGCCCAAAGTACGTTAACCGCCGCTCACTCATGT TGGCCACTGGGATGAGAAACGTCCCGGAACTGATTCAGGGCCGGGGCCTGTTTGGCGCAAT CGCTGGGTTCTTAGAGAACGGCTGGGAGGGCATGGTGGACGGATGGTACGGGTTCCGCCAT CAGAACGCTCAAGGCACTGGGCAGGCTGCAGATTACAAGAGTACCCAGGCTGCCATTGATC AGATTACCGGAAAACTGAATAGGCTGGTCGAAAAGACAAACACTGAGTTCGAAAGCATCGA GAGCGAATTTTCTGAGATCGAGCACCAGATCGGGAATGTGATTAACTGGACTAAAGATAGC ATAACGGATATTTGGACATATCAAGCAGAGTTGTTGGTGGCCATGGAGAATCAGCATACAA TCGACATGGCCGATAGTGAAATGCTGAATCTTTATGAAAGGGTACGGAAGCAGCTGCGCCA AAACGCCGAGGAAGATGGGAAGGGGTGTTTTGAAATCTATCATGCCTGTGACGATTCCTGC ATGGAATCTATTCGTAATAATACTTACGACCATAGCCAATATCGAGAGGAGGCATTGTTGA ACAGGCTAAACATCAATCCGGTGACACTCAGTTCCGGATATAAAGATATAATCCTCTGGTT CTCTTTTGGCGCTTCTTGTTTCGTGCTGCTTGCTGTCGTAATGGGACTGTTCTTTTTTTGT CTCAAAAACGGCAACATGAGATGCACCATTTGCATA 813 ATGTATAAAATCGTTGTGATCATTGCCCTGCTGGGCGCCGTAAAGGGCCTGGACAAAATAT GCCTGGGGCACCATGCAGTAGTGAATGGCACAATTGTCAAGACACTCACTAACGAACAGGA AGAAGTCACCAATGCCACGGAGACGGTGGAGAGTACCGGTCTGAACCGTCTGTGCATGAAG GGCCGCAACCATAAAGACTTGGGTAACTGTCATCCTATAGGTATGCTAATCGGTACTCCGG CCTGCGATCTGCACCTCACCGGTACCTGGGACACCCTGATCGAGCGTGAGAACGCGATCGC CTATTGCTATCCAGGCGCTACTGTAAATGAGGAAGCCCTGAGACAGAAGATCATGGAGTCC GGAGGGATCAATAAGATCTCTACTGGATTCACCTATGGCAGCAGTATTAACTCCGCCGGAA CTACGCGGGCCTGCATGAGAAATGGCGGGAATAGCTTCTACGCTGAACTGAAATGGCTCGT TTCGAAGTCAAAAGGACAGAACTTCCCTCAGACAACGAACACATACCGCAACACCGACACC GCGGAGCATCTAATCATGTGGGGTATCCATCACCCCAGCTCTACACAGGAAAAAAATGATC TTTATGGAACCCAGTCTTTGTCCATTTCTGTGGGCAGCTCCACCTACCAGAACAATTTCGT CCCAGTCGTGGGCGCGCGGCCACAGGTGAACGGACAGTCGGGGCGCATTGACTTTCACTGG ACCCTGGTGCAGCCCGGTGACAATATCACTTTTTCTCACAACGGCGGACTTATTGCTCCCT CCCGGGTGAGCAAACTGATCGGGCGGGGGCTGGGGATCCAGTCCGATGCACCTATCGATAA CAATTGCGAGAGTAAATGCTTCTGGCGTGGGGGATCAATAAATACCAGGCTCCCATTCCAA AATCTTTCACCCCGTACAGTTGGACAGTGCCCCAAATACGTGAACAAGCGCTCTCTTATGC TGGCAACAGGAATGAGAAACGTTCCAGAGCTAATGCAGGGTCGAGGGCTTTTCGGAGCTAT TGCTGGATTTATCGAAAATGGCTGGGAGGGAATGGTCGATGGATGGTATGGATTCCGACAC CAGAACGCTCAGGGGACCGGCCAGGCCGCGGACTACAAGAGCACACAGGCTGCAATTGATC AGATCACAGGGAAGTTAAATAGGCTCATCGAAAAGACGAACACCGAGTTCGAGTCAATCGA GTCCGAATTCTCTGAGATCGAACACCAAATTGGCAATGTCATCAATTGGACAAAGGATAGT ATCACCGATATTTGGACGTACCAAGCAGAGCTTCTGGTTGCCATGGAGAACCAACACACCA TCGATATGGCCGACAGCGAGATGCTTAATCTGTACGAGCGCGTGCGAAAGCAACTTAGGCA AAACGCCGAAGAAGATGGTAAGGGCTGCTTTGAGATTTATCACGCTTGCGATGACTCCTGC ATGGAGTCTATTAGAAATAATACCTACGATCATTCTCAGTATAGAGAGGAGGCCCTGCTGA ACCGGTTGAACATTAACCCAGTTACACTGAGCTCCGGATACAAAGATATTATTCTGTGGTT TTCCTTTGGCGCGTCCTGCTTTGTGCTGTTAGCCGTGGTGATGGGGCTGGTATTCTTCTGT CTCAAGAACGGTAATATGCGTTGTACCATATGCATC 814 ATGTATAAGATCGTGGTCATAATTGCACTCTTGGGGGCAGTGAAAGGGCTGGATAAAATTT GTCTGGGACACCACGCCGTTGCTAATGGCACCATCGTGAAAACCCTTACCAACGAGCAGGA AGAGGTTACTAACGCAACCGAGACGGTCGAGTCCACTGGAATCAATCGTCTTTGCATGAAG GGCCGTAAACATAAGGATTTAGGAAATTGTCATCCCATTGGCATGCTGATCGGAACACCTG CCTGCGACCTGCACCTGACAGGGATGTGGGACACGCTGATCGAGAGGGAGAATGCAATTGC GTACTGTTATCCTGGAGCTACCGTGAATGTTGAAGCACTGCGTCAAAAAATCATGGAATCC GGCGGGATCAACAAAATTAGCACTGGGTTCACATATGGAAGCAGCATAAACTCCGCCGGCA CTACAAGGGCCTGCATGAGAAACGGCGGCAATAGTTTCTACGCTGAACTTAAGTGGCTTGT GTCAAAATCAAAGGGGCAAAACTTTCCTCAGACTACAAATACATATAGAAACACTGACACC GCCGAGCACCTGATCATGTGGGGCATTCACCATCCTAGCTCTACCCAGGAGAAAAATGATT TATACGGCACTCAGAGTCTGTCTATTTCTGTGGGGTCGTCCACATATAGAAATAATTTCGT GCCAGTCGTGGGGGCTCGGCCGCAAGTGAATGGGCAGAGTGGTAGAATCGATTTCCACTGG ACACTTGTGCAGCCCGGGGATAACATTACTTTCTCTCATAACGGCGGCCTGATCGCACCCT CCAGGGTGAGTAAACTAATAGGCAGGGGTCTGGGCATTCAGTCCGACGCTCCAATCGATAA CAACTGCGAGTCCAAGTGCTTCTGGCGCGGCGGTTCCATCAACACCCGGTTACCTTTTCAG AACCTGTCCCCCCGCACCGTTGGCCAGTGCCCTAAATACGTAAATCGAAGATCATTAATGC TGGCGACCGGTATGAGGAACGTACCTGAGCTGATTCAGGGGAGGGGGTTATTTGGTGCCAT TGCCGGGTTTCTCGAAAACGGGTGGGAGGGAATGGTTGATGGCTGGTACGGGTTCAGGCAC CAGAATGCCCAGGGCACAGGACAGGCTGCCGATTACAAGAGCACTCAGGCCGCTATTGACC AGATCACCGGCAAGCTGAATCGGCTGGTAGAGAAAACCAATACGGAGTTTGAGTCCATTGA GTCCGAGTTCTCAGAGATCGAGCACCAGATTGGCAATGTCATCAATTGGACCAAGGATTCA ATTACGGATATATGGACATACCAGGCTGAGCTGCTTGTAGCAATGGAGAACCAACATACCA TAGACATGGCTGATTCTGAGATGCTGAACCTCTACGAAAGGGTCAGAAAACAACTCAGACA AAACGCAGAAGAAGACGGGAAAGGGTGTTTCGAAATTTACCATGCTTGTGATGACTCCTGC ATGGAGAGCATCAGAAACAACACTTATGACCACAGCCAGTACCGTGAAGAGGCATTGTTGA ACCGACTCAACATCAACCCTGTTACGCTGTCATCTGGGTATAAAGACATTATTCTATGGTT CTCTTTTGGCGCTTCATGTTTTGTTCTGTTGGCGGTAGTGATGGGTCTGTTCTTTTTCTGT TTAAAAAATGGCAATATGAGGTGCACCATCTGCATA 815 ATGTACAAGATCGTGGTTATTATCGCTCTTCTGGGTGCCGTTAAAGGGCTGGACAAAATTT GTCTGGGGCATCACGCCGTGGCGAATGGTACTATCGTCAAGACATTGACCAACGAGCAGGA GGAGGTTACAAATGCAACCGAGACCGTTGAGAGTACTGGAATCAACCGGCTGTGCATGAAG GGAAGAAAGCACAAGGATCTGGGGAATTGTCACCCTATCGGAATGTTAATTGGTACACCTG CTTGTGACCTGCACCTGACAGGCATGTGGGACACCCTGATCGAACGGGAGAACGCCATTGC CTATTGTTATCCAGGGGCCACTGTTAATGTCGAGGCACTCAGGCAGAAGATTATGGAATCC GGTGGAATTAATAAAATTAGCACAGGGTTTACTTACGGTTCCTCAATAAATTCAGCCGGCA CTACACGGGCGTGTATGAGGAATGGAGGAAACTCCTTCTATGCCGAACTGAAATGGCTCGT CAGCAAATCCAAGGGTCAAAATTTTCCTCAAACAACTAACACCTATAGAAATACCGATACC GCAGAGCACCTCATAATGTGGGGGATACACCATCCGAGCTCCACACAAGAAAAAAACGACC TGTATGGCACTCAAAGTCTTAGCATTTCCGTCGGAAGTTCTACATACCGGAATAACTTTGT GCCGGTGGTAGGTGCCCGACCCCAAGTCAACGGCCAGAGTGGCCGCATCGATTTCCATTGG ACACTGGTGCAGCCAGGAGATAACATTACCTTTTCTCACAATGGCGGCTTGATCGCTCCTT CGAGGGTGAGCAAGCTGATTGGCCGGGGTCTGGGCATTCAATCCGACGCGCCTATCGACAA TAATTGTGAGTCTAAATGCTTTTGGAGAGGAGGGTCAATCAACACAAGACTACCCTTCCAG AATCTTTCCCCCCGAACAGTGGGACAGTGCCCCAAATATGTGAATCGGCGCTCTCTTATGC TGGCCACTGGGATGAGAAACGTGCCTGAGTTAATACAGGGCCGGGGACTTTTCGGAGCAAT CGCCGGATTCCTAGAGAACGGTTGGGAGGGGATGGTCGACGGATGGTACGGGTTCAGACAC CAAAATGCTCAGGGGACAGGGCAGGCAGCAGACTATAAATCAACGCAGGCCGCTATCGACC AGATCACCGGTAAACTGAACCGGCTTGTCGAAAAGACCAACACTGAGTTCGAGAGTATTGA ATCCGAGTTTAGCGAGATCGAACACCAGATAGGCAATGTTATCAATTGGACAAAGGATTCA ATCACGGACATATGGACATACCAAGCAGAACTGCTGGTAGCTATGGAAAATCAACATACAA TCGATATGGCCGACTCAGAGATGCTCAACCTCTACGAAAGAGTAAGGAAACAACTCAGACA AAATGCCGAAGAGGACGGCAAGGGTTGCTTTGAAATATATCATGCGTGCGACGACAGCTGC ATGGAGAGCATACGGAACAATACGTACGACCATTCCCAGTATCGCGAAGAAGCCTTACTGA ACCGCTTGAACATTAACCCCGTGACCCTTTCCTCCGGATATAAAGATATCATTCTCTGGTT CAGTTTTGGAGCCTCATGCTTTGTCCTTTTGGCTGTGGTAATGGGATTATTTTTCTTCTGT CTCAAGAATGGTAACATGCGATGTACAATTTGCATC 816 ATGTACAAGATCGTGGTGATCATAGCACTGCTGGGCGCCGTGAAAGGCTTAGACAAAATCT GCTTAGGGCATCATGCCGTCGCTAATGGGACTATAGTCAAGACATTGACCAACGAGCAAGA AGAGGTGACAAACGCAACTGAAACTGTTGAAAGTACCGGGATAAACCGGTTGTGCATGAAA GGGCGAAAGCACAAGGACCTTGGCAACTGTCATCCCATCGGCATGCTTATAGGAACACCTG CTTGCGATCTCCATCTGACTGGCATGTGGGACACCCTGATAGAACGAGAAAATGCCATTGC CTACTGTTACCCAGGCGCCACCGTTAATGTTGAGGCCCTCAGACAGAAGATAATGGAATCT GGAGGCATCAACAAAATCTCTACGGGCTTTACCTACGGTTCTAGCATTAACTCTGCCGGGA CTACCCGAGCTTGTATGCGCAACGGGGGCAACTCTTTCTACGCCGAACTTAAGTGGCTGGT GAGCAAGAGCAAGGGACAGAATTTCCCTCAAACTACTAACACTTATAGGAACACAGACACC GCCGAACATCTAATAATGTGGGGAATACACCATCCCTCATCCACACAGGAAAAAAACGACC TTTATGGGACCCAGTCTCTGAGCATTTCAGTCGGCTCATCCACTTATCGTAACAACTTTGT GCCCGTGGTTGGGGCTCGGCCCCAGGTGAATGGCCAGTCTGGGCGTATTGATTTCCACTGG ACCCTAGTGCAACCCGGAGACAACATCACCTTTAGTCATAATGGTGGCCTTATAGCCCCTA GCAGGGTGTCAAAACTTATTGGGAGAGGCCTCGGGATTCAGAGTGACGCACCCATCGACAA CAACTGCGAGAGTAAGTGTTTTTGGAGAGGGGGTTCGATCAACACCCGCCTCCCCTTCCAG AACCTATCGCCACGCACTGTTGGTCAGTGCCCAAAATACGTCAACAGGAGGTCACTTATGC TGGCTACAGGGATGCGGAACGTGCCGGAGCTGATACAGGGACGCGGTCTGTTCGGAGCCAT TGCCGGATTCTTGGAGAATGGCTGGGAGGGGATGGTGGACGGCTGGTACGGCTTCCGACAC CAGAATGCCCAGGGTACAGGTCAGGCAGCGGACTATAAGAGTACTCAAGCCGCTATCGATC AAATCACTGGGAAGCTCAACCGACTGGTCGAGAAGACAAACACAGAATTCGAGTCTATCGA GTCAGAATTCTCTGAAATCGAGCACCAGATTGGTAACGTAATCAATTGGACCAAGGATAGT ATTACCGACATCTGGACATACCAAGCAGAACTGCTCGTGGCAATGGAAAATCAGCACACAA TAGACATGGCCGATAGTGAGATGCTCAACCTGTACGAACGCGTTCGAAAACAGCTGAGACA GAACGCTGAAGAAGACGGGAAAGGGTGCTTCGAGATCTATCACGCCTGCGACGATTCATGC ATGGAGAGCATTAGAAACAATACCTACGACCACAGCCAGTATAGGGAGGAGGCTCTGCTAA ACAGGCTCAACATTAATCCCGTAACACTCTCAAGCGGATATAAAGACATAATTCTGTGGTT TTCCTTCGGAGCTTCCTGCTTCGTCCTGCTGGCGGTAGTCATGGGGTTATTCTTTTTTTGT CTGAAGAACGGGAATATGCGATGTACAATATGCATT 817 ATGTACAAGGTTGTGGTTATTATAGCACTCCTCGGGGCTGTGCGCGGACTGGATAAGATCT GCCTGGGACATCATGCCGTGGCAAATGGTACCACTGTAAAAACTCTCACCAATGAGCAGGA AGAGGTGACCAACGCCACTGAGACAGTGGAATCTACAAGCCTGAACAAGCTGTGTATGAAG GGCAGACGATATAAGGATCTGGGTAATTGCCATCCCATCGGCATGTTGATCGGAACACCAG TTTGCGATCTGCATCTAACTGGAACCTGGGACACGCTTATCGAGCGGGAAAACGCCACCGC GTACTGCTACCCAGGAGTCACCATCAACGAAGAAGCACTGAGACAGAAGATCATGGAGAGT GGGGGGATCTCCAAGATGCGCACCGGGTTCACTTATGGGCCCAGCATTAACAGCGCTGGGA CAACCAGATCCTGCATGAGGAATGGAGGGAACTCTTTTTATGCCGAATTAAAATGGCTGGT TTCAGGAACAAAAGGACAAAATTTCCCGCAGACCACCAATACATATAGAAACACCGATACA GCAGAACACTTAATCATCTGGGGGATCCATCACCCTTCATCTACGCAGGAAAAGAATGATC TGTATGGTACCCAGTCTTTGAGTATTAGTGTAGGCTCTTCCACGTACCAGAATAACTTTGT CCCTGTTATAGGTGCTCGACCTCAGGTCAATGGGCAGTCTGGGCGTATCGAGTTCCATTGG ACCCTCGTACGACCCGGCGACAACATCACATTTAGCCACAACGGCGGATTGATAGCCCCCG ACAGAGTGTCCAAGTTAATCGGCAAAGGAATTGGTATCCAGTCCGGCGCCGTGATCGATAA GGATTGTGAGTCAAAATGCTTCTGGAGAGGCGGCAGCATCATAACAGAGCTTCCGTTTCAA AACCTGAGTCCCCGCACCGTTGGGCAATGTCCTAAGTACGTGAAAAAACGAAGCCTCCTGC TGGCAACCGGCATGCGGAATGTTCCCGAGGTGGTCCAGGGAAGAGGCCTGTTTGGCGCGAT TGCTGGGTTCATCGAGAATGGCTGGGAAGGCATGGTTGACGGATGGTATGGGTTCAGGCAT CAGAACGCGCAGGGCATCGGGCAGGCTGCTGACTACAAGAGCACTCAGACCGCCATCGATC AGATCACAGGGAAGCTAAATCGGCTGATTGAAAAGACTAACACGGAGTTTGAGAGCATTGA AAGCGAATTTAGTGAAATCGAACACCAGATAGGAAACGTTATTAACTGGACAAAGGATAGT ATTACCGACATATGGACGTATCAAGCAGAGCTGCTGGTCGCCATGGAGAACCAGCATACTA TAGATATGGCAGACAGCGAAATGCTCAATTTGTACGAGAGGGTAAGAAAACAACTGAGACA AAATGCTGAAGAGGATGGCAAAGGCTGCTTTGAAATATACCACACCTGTGACAATTCCTGT ATGGAGTCCATTCGGAACAATACGTATGATCATTCCCAGTATCGCGAGGAAGCCCTACTCA ACCGCCTCAATATCAACCCCGTTAAGCTATCATCAGGCTACAAGGACATTATCCTGTGGTT CAGCTTCGGAGCCTCCTGTTTCGTGCTACTTGCTGTGATCATGGGTTTGGGGTTCTTTTGC CTGAAAAATGGAAATATGAGATGCACAATTTGTATT 818 ATGTATAAGATAGTCGTGATAATCGCCCTTTTGGGAGCGGTGAAGGGACTGGACAAGATTT GTCTCGGCCATCATGCAGTCGCCAACGGTACAATTGTTAAAACCCTCACCAACGAACAAGA AAAAGTGACAAATGCCACAGAAACTGTGGAGAGCACCGGCCTTAACCGGTTGTGCATGAAG GGGCGAAAGCATAAGGACTTGGGTAATTGTCATCCAATTGGGATGCTGATTGGGACTCCCG CCTGCGATCTGCACCTGACCGGCACATGGGATACCATTATCGAGAGGGAGAACGCGATCGC TTACTGCTATCCTGGGGCTACAGTCAATGAGGAGGCCCTAAGGCAGAAAATAATGGAGTCA GGGGGAATCGATAAAATTTCTACAGGCTTCACTTACGGATCTTCTATTAACAGCGCAGGCA CCACGCGCGCCTGCATGAGAAATGGCGGGAATAGTTTTTATGCCGAGCTGAAATGGCTGGT GTCCAAGAGCAAGGGACAGAACTTTCCGCAAACCACTAATACATACCGTAATACTGACACA GCAGAACATCTGATTATGTGGGGAATCCACCACCCCTCCAGCACTCAAGAGAAAAATGATC TTTACGGAACACAGTCCCTCAGCATAAGCGTGGGTTCGAGTACATATAGGAACAATTTCGT GCCAGTGGTAGGCGCGCGACCGCAGGTCAATGGACAGTCAGGAAGGATCGACTTCCATTGG ACTCTAGTGCAACCTGGGGATAATATTACCTTTAGCCATAATGGAGGTCTGATAGCCCCAT CTCGCGTCTCCAAGCTGATTGGGCGCGGTCTGGGGATTCAGAGTGACGCTCCTATTGATAA CAACTGCGAGAGTAAATGTTTCTGGCGCGGCGGCTCGATTAACACCCGTCTTCCCTTTCAG AACCTGAGTCCCCGGACAGTAGGACAGTGCCCTAAATACGTGAACAAAAGAAGTCTTATGC TCGCCACTGGGATGCGAAACGTTCCGGAACTGATCCAGGGTCGCGGCCTGTTCGGCGCAAT TGCTGGTTTCCTCGAAAATGGATGGGAAGGTATGGTGGATGGGTGGTACGGGTTCAGACAT CAAAACGCTCAGGGCACGGGCCAGGCTGCCGACTACAAGAGCACACAGGCTGCCATCGACC AGATTACTGGGAAACTCAATAGACTCGTGGAAAAAACTAATACGGAATTCGAAAGCATCGA ATCTGAGTTCAGTGAGATCGAACATCAGATCGGAAACGTGATCAACTGGACAAAGGATTCG ATTACTGATATTTGGACGTACCAGGCAGAGTTGTTGGTCGCCATGGAGAATCAACACACAA TCGATATGGCCGACTCAGAGATGTTGAATCTTTACGAGAGGGTGCGAAAGCAGCTGAGGCA GAATGCCGAGGAAGATGGAAAGGGGTGTTTTGAGATCTACCACGCCTGCGACGATTCTTGC ATGGAATCCATCCGCAATAATACATACGATCACTCACAGTATAGGGAGGAGGCCCTACTCA ACAGACTGAACATCAATCCCGTGACACTTTCAAGTGGTTACAAGGATATCATACTTTGGTT CAGCTTCGGCGCCAGTTGCTTTGTTCTGCTTGCCGTTGTGATGGGCCTGGTGTTCTTTTGC CTGAAGAATGGTAACATGAGATGTACCATCTGCATT 819 ATGTATAAAATTGTCGTTATCATTGCCTTGCTCGGCGCTGTGAAGGGGCTGGATAAAATTT GTCTGGGACATCACGCCGTGGCGAACGGGACTATCGTCAAGACGCTTACTAACGAACAGGA AGAGGTGACTAACGCGACGGAAACCGTGGAGTCAACTGGGATTAATCGCTTGTGCATGAAG GGCAGAAAGCACAAGGACTTAGGCAACTGTCATCCTATCGGCATGCTGATCGGTACCCCAG CCTGCGACCTTCACTTGACTGGCACCTGGGATACCCTGATCGAAAGAGAGAACGCAATAGC ATACTGTTATCCAGGCGCCACAGCCAACGTAGAGGCCCTGAGACAGAAGATCATGGAATCT GGAGGTATCGATAAAATTAGCACCGGATTTACATATGGATCAAGTATAAACTCGGCAGGAA CGACGCGGGCGTGCATGCGAAATGGCGGAAATTCCTTCTACGCCGAATTGAAATGGCTAGT GTCCAAAAGCAAAGGCCAAAACTTTCCACAGACTACTAACACCTACAGAAATACTGACACC GCTGAACATTTGATTATGTGGGGGATCCACCACCCAAGTAGCATTCAGGAGAAGAACGATC TGTATGGCACTCAGTCACTAAGTATTTCCGTGGGCAGCTCTACCTACCGCAATAACTTCGT GCCGGTTGTGGGCGCCAGACCTCAGGTGAACGGACAAAGTGGTCGCATTGATTTCCACTGG ACACTTGTGCAACCTGGGGACAATATCACTTTCAGCCACAACGGGGGGCTGATCGCCCCAT CAAGAGTGAGCAAATTGATAGGGAGAGGCTTGGGAATCCAGTCAGATGCACCTATCGATAA TAATTGTGAAAGCAAATGCTTTTGGCGTGGGGGATCCATAAACACTCGACTGCCATTCCAG AATTTGTCCCCCCGCACCGTTGGCCAGTGTCCCAAGTACGTTAATCGCAGAAGTCTGATGC TGGCCACCGGCATGAGAAACGTGCCCGAACTGATACAGGGACGCGGGCTCTTTGGAGCAAT TGCCGGCTTTCTGGAGAACGGATGGGAGGGAATGGTGGACGGATGGTACGGCTTTCGGCAC CAGAATGCCCAGGGGACAGGACAAGCCGCCGATTATAAGTCAACACAGGCCGCAATCGACC AGATTACCGGCAAGCTCAACAGGCTCGTGGAAAAGACAAACACTGAGTTTGAGTCAATCGA GTCAGAATTTTCCGAGATCGAGCATCAAATCGGCAACGTGATCAATTGGACTATGGATTCT ATCACCGACATTTGGACTTACCAGGCAGAGCTCCTGGTGGCAATGGAGAACCAACACACTA TCGACATGGCAGATTCAGAGATGCTCAACCTCTATGAAAGGGTACGAAAACAGCTTCGGCA GAACGCCGAGGAGGACGGTAAGGGGTGTTTTGAAATCTATCATGCGTGCGACGATAGCTGT ATGGAAAGTATCCGGAATAATACATACGATCACTCCCAGTACCGCGAAGAGGCTCTCTTGA ACCGGCTTAACATCAACCCGGTAACTCTCAGTAGCGGGTACAAGGACATCATTCTGTGGTT TTCTTTTGGTGCCTCCTGTTTTGTGCTGCTGGCCGTGGTGATGGGACTCGTGTTTTTTTGC CTCAAGAACGGGAATATGCGGTGCACAATATGCATT 820 ATGTATAAGATTGTGGTGATTATTGCTCTCTTGGGGGCAGTCAAAGGACTTGATAAGATTT GTCTGGGCCACCATGCTGTCGCAAATGGGACAATCGTCAAGACCCTTACCAACGAGCAAGA AAAGGTAACCAACGCAACCGAGACTGTTGAGAGTACAGGGCTGAATAGACTCTGTATGAAG GGCCGCAAACATAAGGACCTAGGTAACTGTCATCCAATAGGGATGCTGATTGGAACACCGG CATGTGACTTACACCTCACAGGTACATGGGATACTATTATAGAGAGAGAAAATGCCATTGC CTACTGTTATCCTGGGGCTACCGTTAACGAGGAAGCCTTACGTCAGAAAATTATGGAATCC GGGGGCATTGATAAAATATCCACTGGATTTACTTATGGAAGCTCAATCAACTCCGCGGGCA CTACTCGAGCATGTATGCGCAACGGAGGTAACTCCTTCTACGCCGAACTGAAGTGGCTCGT TTCAAAATCCAAAGGACAGAACTTTCCGCAGACCACTAATACCTACCGCAATACAGACACA GCAGAACATCTGATCATGTGGGGCATTCATCACCCCAGCTCTACTCAAGAAAAGAATGACC TGTACGGGACTCAAAGTCTGTCCATTTCTGTTGGGTCTAGTACCTACCGGAATAACTTTGT CCCCGTTGTTGGAGCACGCCCTCAGGTTAACGGTCAGAGTGGAAGGATCGACTTTCACTGG ACCCTCGTCCAGCCTGGCGACAATATCACATTTAGTCACAACGGGGGCCTAATCGCTCCCT CTCGGGTGAGCAAGCTGATAGGTCGGGGCTTGGGTATACAGTCTGACGCCCCAATCGATAA CAACTGTGAAAGCAAGTGCTTCTGGCGGGGTGGCTCTATCAACACCCGACTGCCATTTCAA AATCTCAGTCCAAGGACAGTGGGGCAATGCCCAAAATACGTCAACAAAAGGTCACTCATGC TCGCCACAGGAATGCGCAATGTGCCTGAACTGATTCAAGGACGAGGACTGTTTGGCGCTAT TGCCGGGTTTTTAGAGAATGGCTGGGAAGGCATGGTAGACGGGTGGTACGGGTTCCGGCAT CAGAATGCCCAAGGGACGGGTCAGGCCGCTGACTATAAGTCCACTCAGGCCGCAATAGATC AGATCACCGGAAAGTTGAACAGACTAGTGGAGAAGACAAACACTGAGTTCGAGTCCATTGA GAGCGAATTCAGCGAGATAGAACACCAAATCGGCAATGTGATTAACTGGACCAAAGACAGT ATTACTGATATCTGGACTTATCAAGCCGAACTGTTGGTGGCAATGGAGAACCAACACACGA TCGACATGGCAGACAGTGAGATGCTCAATCTGTACGAGAGGGTGCGTAAACAGCTGAGGCA GAACGCCGAAGAAGACGGAAAGGGGTGTTTCGAGATATACCACGCCTGTGATGACTCCTGT ATGGAAAGCATCAGGAACAACACTTATGACCATAGTCAATATAGGGAAGAAGCACTGCTCA ACCGCCTGAACATCAATCCTGTAACACTTTCATCAGGATATAAGGACATCATCCTCTGGTT TAGTTTCGGAGCTTCATGCTTTGTGCTGCTCGCGGTAGTCATGGGGCTGGTCTTCTTTTGT TTGAAGAACGGTAACATGAGATGCACCATTTGTATC 821 ATGTACAAAATCGTCGTCATCATCGCCTTACTGGGAGCCGTCAAAGGACTTGATAAAATTT GTCTTGGTCACCACGCTGTTGCCAATGGAACAATCGTGAAGACACTTACCAATGAGCAGGA GGAGGTGACTAATGCAACAGAGACAGTGGAGTCCACTGGAATAAATCGGCTGTGCATGAAG GGCAGAAAACACAAGGATTTGGGCAACTGCCACCCTATTGGAATGCTCATAGGCACCCCTG CGTGTGACCTTCATCTGACTGGCACTTGGGACACTCTCATCGAACGCGAGAACGCCATCGC CTACTGCTATCCTGGAGCCACCGCCAACGTGGAGGCTCTACGGCAGAAGATTATGGAGAGC GGAGGGATTGACAAGATCTCCACGGGTTTCACTTACGGCAGCTCCATCAACAGTGCCGGTA CAACTCGGGCGTGCATGAGAAACGGGGGCAACAGCTTTTATGCCGAGCTGAAGTGGCTGGT GAGTAAGTCAAAAGGGCAGAACTTTCCACAGACAACAAATACGTACAGAAATACAGATACA GCCGAGCACCTGATCATGTGGGGGATTCATCATCCAAGTTCTATCCAGGAGAAAAACGACT TGTATGGGACTCAGAGTCTCAGTATCAGCGTAGGTTCCTCTACCTACAGGAACAACTTCGT GCCCGTCGTCGGGGCCCGTCCCCAAGTCAACGGCCAGAGTGGACGGATTGATTTTCACTGG ACTCTTGTGCAGCCCGGCGACAACATTACCTTCAGTCACAACGGAGGGCTGATTGCACCTT CCAGAGTCTCGAAGCTGATCGGACGTGGATTGGGGATTCAGTCGGACGCTCCTATCGACAA TAATTGCGAGAGCAAATGTTTCTGGCGCGGGGGTTCTATTAACACCAGGCTCCCCTTTCAA AATTTGAGCCCGCGAACCGTCGGCCAATGTCCCAAGTATGTCAACCGGAGAAGCCTGATGT TGGCTACAGGAATGCGCAATGTGCCGGAGCTCATCCAGGGCCGTGGCTTGTTCGGTGCAAT TGCCGGATTCCTAGAAAATGGATGGGAGGGAATGGTTGATGGGTGGTACGGCTTCCGCCAC CAAAACGCTCAGGGCACTGGACAGGCCGCGGACTATAAGTCTACTCAGGCGGCTATCGATC AGATCACTGGGAAACTGAATAGGCTTGTGGAAAAAACCAATACGGAGTTCGAAAGTATCGA GTCAGAGTTTAGCGAAATCGAGCATCAGATTGGTAACGTGATCAACTGGACCATGGATAGC ATTACCGACATCTGGACCTACCAGGCCGAATTGCTGGTGGCCATGGAGAATCAGCACACAA TTGACATGGCAGACTCTGAAATGCTTAACCTATATGAGCGCGTACGGAAACAGCTCAGACA GAACGCGGAGGAAGATGGAAAGGGCTGCTTCGAAATTTATCACGCTTGCGACGACTCCTGT ATGGAGTCTATCAGAAACAATACGTATGATCATTCGCAATACCGGGAGGAAGCACTCCTGA ATAGACTCAACATCAACCCCGTTACACTGAGCTCAGGGTACAAAGACATTATTCTCTGGTT TTCCTTCGGAGCTTCTTGCTTCGTACTGTTAGCTGTCGTCATGGGGCTAGTTTTTTTTTGT CTTAAAAACGGCAACATGAGATGCACCATCTGTATA 822 ATGTATAAAATCGTGGTAATCATTGCACTGCTGGGAGCAGTCAAAGGGCTCGATAAAATAT GCCTTGGCCACCACGCCGTAGCAAATGGTACAATCGTGAAGACCCTCACGAACGAACAGGA GGAAGTCACCAACGCTACAGAAACTGTCGAAAGTACCGGGATCAACCGGCTCTGTATGAAG GGCAGGAAGCATAAAGACTTAGGTAACTGCCATCCTATCGGCATGCTGATTGGCACACCTG CCTGCGACTTGCACTTAACGGGAATGTGGGACACATTGATTGAGAGAGAGAATGCTATTGC TTACTGTTACCCAGGAGCGACTGTGAACGTGGAGGCACTACGGCAAAAAATAATGGAGTCC GGGGGAATCAATAAGATCTCGACAGGATTTACCTATGGGAGCTCAATCAATTCTGCGGGAA CAACCCGGGCCTGCATGCGCAATGGCGGGAATAGCTTCTATGCCGAACTCAAGTGGCTCGT TAGCAAGAGCAAAGGGCAGAATTTCCCGCAAACTACTAACACATACAGGAACACAGACACA GCAGAGCATTTGATTATGTGGGGGATTCACCACCCCTCTAGTACGCAGGAAAAGAACGATC TTTACGGGACCCAGTCCCTTTCTATCAGCGTAGGAAGCAGCACTTACAGGAATAATTTTGT CCCTGTGGTTGGCGCGGGCCCTCAGGTTAATGGGCAATCTGGCCGCATTGATTTTCATTGG ACCCTCGTACAGCCTGGCGACAATATAACATTCTCACATAATGGCGGCCTGATCGCACCTT CCCGGGTATCTAAATTGATAGGTAGAGGCCTGGGGATTCAAAGCGATGCTCCAATAGATAA TAACTGTGAATCAAAGTGCTTTTGGCGGGGAGGGTCAATTAATACGCGGCTACCCTTTCAG AATCTTAGCCCACGCACCGTTGGCCAATGTCCAAAGTACGTGAATCGTAGATCACTGATGC TGGCTACAGGGATGCGGAATGTGCCAGAACTCATTCAGGGCCGTGGGCTATTCGGCGCTAT CGCCGGGTTTCTGGAAAACGGCTGGGAGGGGATGGTCGATGGCTGGTACGGCTTCCGGCAC CAGAACGCTCAGGGTACAGGGCAGGCGGCTGATTATAAAAGCACACAGGCTGCAATCGACC AAATTACTGGAAAACTAAATAGGCTAGTGGAAAAAACCAACACCGAATTCGAAAGTATTGA AAGTGAGTTCAGTGAAATTGAGCACCAGATTGGAAACGTGATCAACTGGACTAAGGACAGT ATCACCGATATTTGGACATATCAGGCAGAACTTCTCGTGGCCATGGAAAACCAGCATACTA TTGACATGGCTGACAGTGAAATGTTAAATCTCTATGAGCGCGTACGCAAACAATTGCGGCA GAATGCCGAGGAAGATGGGAAGGGCTGCTTCGAAATCTATCACGCTTGCGACGATTCCTGC ATGGAGTCCATCAGGAACAATACATACGATCACAGCCAGTATCGCGAAGAAGCCCTGCTTA ATAGACTAAATATTAATCCCGTCACCCTGTCCTCAGGCTATAAGGACATCATCCTTTGGTT TTCATTTGGCGCAAGTTGCTTCGTCTTGCTCGCAGTCGTCATGGGGCTGTTTTTTTTCTGT CTCAAAAACGGAAACATGAGGTGTACCATTTGCATT 823 ATGTACAAAATTGTGGTTATCATCGCTTTGCTTGGCGCTGTGAAGGGGCTGGATAAGATCT GTCTCGGGCATCACGCTGTCGCCAATGGCACAATTGTCAAGACATTGACGAACGAGCAGGA GGAAGTGACAAATGCCACTGAAACAGTGGAATCCACTGGGATCAACCGATTGTGCATGAAA GGTAGGAAGCATAAGGATCTCGGTAACTGTCATCCAATCGGCATGTTGATTGGAACCCCGG CCTGTGATCTTCACCTCACTGGTATGTGGGACACACTGATTGAAAGAGAAAACGCTATTGC CTACTGTTACCCAGGTGCAACGGTTAATGTCGAGGCACTGAGACAGAAAATTATGGAAAGC GGAGGCATCAACAAGATATCAACCGGGTTTACCTATGGCTCATCGATTAATAGCGCAGGCA CCACTCGCGCGTGTATGCGAAATGGAGGAAATTCATTTTATGCCGAGTTAAAATGGCTGGT TAGTAAGAGCAAGGGTCAGAACTTCCCTCAGACCACAAATACGTATCGCAATACGGACACT GCAGAACACCTTATCATGTGGGGTATTCACCACCCTAGCAGTACTCAAGAAAAAAATGACC TGTATGGTACCCAGAGTCTGAGTATAAGCGTGGGTTCCAGTACTTACCGGAACAACTTCGT TCCAGTTGTGGGGGCCCGCCCACAGGTTAACGGGCAATCGGGGCGCATCGATTTTCACTGG ACCTTGGTGCAACCTGGAGACAATATTACTTTCAGTCACAACGGCGGATTGATAGCTCCAT CCCGTGTCAGTAAATTGATTGGGCGCGGACTGGGAATCCAGTCTGACGCACCCATAGATAA CAACTGTGAGTCTAAGTGTTTCTGGAGGGGCGGTTCCATTAATACTCGGCTGCCATTTCAG AATCTTAGCCCGCGCACTGTGGGTCAATGTCCCAAGTACGTGAACAGGCGTTCTCTAATGC TTGCCACCGGGATGAGAAACGTTCCTGAACTGATACAAGGTAGGGGACTGTTCGGTGCAAT CGCTGGCTTTTTGGAGAATGGCTGGGAGGGAATGGTGGACGGCTGGTATGGATTCCGCCAT CAGAACGCCCAGGGAACCGGACAGGCTGCCGACTATAAGTCCACGCAGGCCGCGATTGACC AAATTACCGGAAAACTCAATCGCCTAGTCGAGAAAACAAACACCGAATTCGAGAGTATCGA GTCCGAATTTTCTGAGATCGAGCACCAAATCGGCAACGTAATCAATTGGACGAAGGATTCC ATTACTGACATCTGGACCTACCAAGCCGAATTGTTGGTCGCAATGGAGAACCAGCACACCA TAGACATGGCTGACAGCGAAATGCTGAACCTGTACGAGCGGGTTCGGAAACAGCTGCGCCA GAACGCAGAGGAGGATGGCAAAGGCTGCTTCGAAATCTATCACGCCTGCGACGATAGCTGC ATGGAATCAATAAGGAATAACACTTATGATCACAGCCAGTATCGGGAAGAGGCCCTGCTGA ATCGGCTCAACATCAATCCCGTGACTCTCTCTTCCGGCTATAAAGACATTATCTTGTGGTT CTCTTTCGGCGCGTCATGCTTCGTGCTGCTGGCAGTGGTAATGGGACTCTTCTTTTTTTGC CTGAAAAACGGGAACATGCGCTGCACAATCTGCATC 824 ATGTATAAGATTGTGGTGATTATTGCCCTGCTCGGCGCCGTGAAGGGGTTGGACAAGATTT GTCTTGGTCACCACGCCGTGGCTAACGGGACCATAGTCAAGACTCTGACCAATGAACAGGA AGAGGTAACAAACGCAACCGAAACAGTCGAGTCTACAGGAATCAATCGGTTATGTATGAAA GGCCGAAAACATAAAGACCTCGGCAATTGTCACCCCATAGGGATGCTGATCGGGACTCCAG CTTGCGACCTGCATTTAACAGGCATGTGGGACACTCTCATCGAGAGAGAGAACGCGATCGC ATACTGCTACCCAGGAGCTACCGTGAATGTAGAGGCATTGAGACAGAAAATCATGGAAAGT GGCGGAATAAATAAGATTTCTACAGGGTTTACGTACGGCAGCTCCATTAACAGTGCCGGAA CAACCCGAGCATGTATGAGAAATGGAGGTAATAGCTTTTACGCCGAACTGAAGTGGCTTGT GTCCAAAAGTAAGGGGCAAAATTTTCCTCAGACAACGAACACCTACCGGAACACCGACACA GCTGAGCACCTGATTATGTGGGGGATACATCATCCTAGCAGCACGCAGGAGAAGAATGATC TATACGGGACCCAATCTCTCAGCATCTCAGTGGGCTCCTCAACTTACCGCAACAACTTCGT GCCTGTCGTCGGCGCCCGCCCTCAGGTCAACGGTCAGTCTGGCCGAATCGACTTTCACTGG ACACTGGTGCAGCCTGGAGACAACATCACTTTCTCCCATAACGGGGGACTTATCGCACCGA GCAGAGTGAGCAAGCTGATTGGAAGAGGACTCGGAATACAATCCGATGCCCCGATAGATAA TAATTGTGAGAGCAAGTGTTTCTGGCGCGGCGGATCCATCAATACACGCTTACCGTTTCAG AACTTGAGCCCACGGACTGTTGGGCAGTGCCCAAAGTACGTGAACCGCCGCAGTTTAATGC TTGCTACCGGTATGAGAAATGTACCTGAACTCATTCAAGGCAGGGGCCTGTTTGGCGCAAT CGCTGGCTTTCTCGAAAATGGATGGGAAGGCATGGTAGACGGTTGGTACGGATTCAGACAC CAGAATGCCCAGGGCACGGGTCAAGCAGCCGATTATAAAAGCACACAAGCAGCAATTGATC AGATTACAGGTAAGCTCAACCGTCTCGTGGAAAAAACTAACACCGAGTTCGAATCCATTGA GAGTGAGTTCAGTGAGATAGAGCACCAGATCGGAAATGTGATTAACTGGACAAAAGATAGC ATTACAGATATCTGGACGTACCAGGCTGAGCTCTTGGTGGCGATGGAAAATCAGCATACCA TTGACATGGCCGACTCAGAGATGCTTAACCTGTATGAGAGAGTGCGCAAACAGCTTAGACA GAACGCCGAAGAGGATGGCAAGGGATGTTTCGAGATCTACCACGCTTGTGATGACAGCTGT ATGGAGAGTATTAGAAACAACACGTATGACCATTCCCAGTACCGAGAGGAGGCTTTGCTTA ATCGTTTGAATATTAACCCCGTCACGCTCAGCAGCGGGTACAAAGATATCATACTCTGGTT CTCTTTCGGAGCATCATGCTTCGTACTTTTGGCTGTGGTGATGGGGCTGTTTTTCTTCTGC TTGAAAAACGGCAACATGAGGTGCACTATCTGTATC 825 ATGTACAAAATCGTTGTGATCATTGCTCTGTTGGGCGCGGTAAAGGGCCTAGATAAGATTT GTCTGGGCCATCACGCCGTTGCCAACGGCACTATAGTTAAAACGCTGACAAATGAACAGGA AAAGGTAACTAACGCCACCGAGACTGTGGAGTCCACTGGTCTGAACCGACTCTGCATGAAA GGGCGAAAACATAAAGACCTGGGCAACTGTCACCCAATTGGGATGCTGATCGGGACACCTG CCTGCGATCTCCACCTGACCGGTACATGGGACACAATCATTGAAAGGGAAAACGCCATCGC CTACTGTTATCCAGGCGCTACAGTCAACGAGGAAGCATTGCGGCAGAAAATTATGGAGTCT GGCGGAATCGATAAGATATCCACTGGCTTCACCTACGGATCGTCTATTAACTCTGCGGGTA CGACACGCGCCTGTATGAGGAACGGCGGAAATAGCTTTTACGCTGAACTAAAGTGGTTAGT TTCTAAGAGCAAGGGCCAGAATTTCCCACAGACCACAAATACATACAGGAATACAGATACC GCTGAGCATCTAATCATGTGGGGAATACACCACCCCTCGTCAACTCAGGAGAAGAATGATC TGTATGGCACACAGTCTCTGTCAATTTCCGTGGGCTCAAGCACATATAGGAACAACTTCGT GCCTGTTGTTGGCGCCAGACCCCAAGTCAATGGCCAGTCTGGAAGGATTGACTTCCATTGG ACCCTGGTCCAACCCGGGGATAATATCACCTTTTCCCATAATGGAGGGCTGATCGCGCCTA GTCGCGTCAGTAAACTCATCGGGAGAGGGCTGGGAATTCAATCAGATGCCCCCATTGATAA CAACTGTGAAAGTAAATGCTTTTGGCGGGGGGGTTCCATCAATACACGCCTGCCATTTCAG AATCTGAGCCCCAGGACGGTTGGTCAGTGCCCCAAGTACGTGAACAAGAGAAGCCTGATGC TGGCAACTGGGATGCGCAATGTTCCTGAACTGATTCAGGGACGCGGGTTATTTGGAGCTAT TGCCGGTTTTCTCGAGAATGGCTGGGAGGGAATGGTCGATGGGTGGTACGGATTTAGACAC CAAAACGCTCAGGGAACAGGCCAGGCGGCTGATTACAAAAGCACCCAGGCCGCTATTGATC AGATCACTGGAAAACTGAACCGCCTTGTCGAGAAAACAAACACCGAATTTGAGAGCATAGA GTCCGAATTCTCAGAGATTGAACATCAAATTGGCAACGTGATAAATTGGACTAAAGACTCC ATTACCGACATCTGGACCTACCAGGCCGAGCTCTTGGTTGCTATGGAAAATCAGCATACTA TCGACATGGCCGACTCTGAAATGCTTAATCTGTACGAACGCGTGAGAAAACAGTTACGCCA GAACGCGGAGGAAGATGGCAAAGGGTGCTTCGAGATCTACCATGCATGCGATGACAGCTGT ATGGAAAGCATCCGTAATAATACCTATGATCACTCTCAGTATAGGGAAGAGGCCCTGTTGA ATAGATTAAACATTAACCCAGTGACACTGAGCAGCGGCTATAAGGACATTATTTTATGGTT TTCCTTTGGAGCAAGTTGTTTTGTGCTGCTGGCGGTGGTGATGGGGCTCGTGTTCTTTTGC CTGAAGAATGGTAACATGCGCTGTACTATCTGTATT 826 ATGTACAAGATAGTCGTGATAATTGCACTCCTCGGCGCAGTTAAGGGCTTGGATAAGATCT GCCTGGGACACCACGCCGTCGCGAACGGCACTATTGTCAAGACTTTAACGAACGAGCAAGA AGAGGTAACAAATGCAACAGAAACTGTTGAGAGCACGGGCATCAATCGGCTGTGCATGAAG GGTAGGAAGCATAAGGACCTGGGAAACTGTCACCCCATCGGCATGCTGATCGGGACCCCCG CATGTGATTTACACCTTACAGGAATGTGGGATACTCTGATCGAAAGAGAGAATGCCATTGC TTACTGTTACCCTGGGGCCACGGTGAACGTGGAGGCCCTTAGGCAGAAAATCATGGAAAGT GGAGGGATCAACAAGATTTCCACCGGTTTCACGTATGGCTCTTCTATTAATTCCGCTGGAA CCACTAGGGCCTGTATGCGAAATGGAGGCAACTCCTTCTACGCTGAATTGAAGTGGCTGGT AAGCAAGTCCAAAGGGCAGAATTTCCCACAGACAACAAACACGTACAGAAACACGGACACC GCTGAGCACCTCATCATGTGGGGCATCCACCACCCTAGCTCTACCCAGGAAAAAAATGATT TATACGGAACGCAGTCTCTTTCAATCTCCGTCGGCTCAAGCACTTATAGAAATAATTTTGT GCCCGTCGTGGGGGCCCGGCCCCAGGTAAACGGCCAATCAGGGAGGATCGACTTTCATTGG ACCCTGGTTCAGCCCGGGGATAACATAACCTTTAGCCATAACGGAGGTCTTATAGCGCCGA GTCGAGTGTCAAAGCTGATCGGGCGCGGTTTGGGCATCCAGTCTGATGCCCCCATCGACAA CAACTGCGAGAGCAAATGCTTTTGGAGGGGAGGGTCCATTAATACCCGTCTGCCATTCCAG AATCTCTCTCCCCGGACCGTCGGCCAGTGCCCCAAATACGTGAATCGTCGTTCTCTCATGC TCGCCACCGGAATGCGCAACGTGCCTGAGTTGATCCAAGGTCGGGGACTGTTCGGGGCCAT TGCCGGCTTTCTGGAGAACGGGTGGGAGGGGATGGTGGATGGCTGGTACGGCTTTAGGCAC CAGAACGCTCAGGGAACTGGGCAGGCGGCCGACTACAAGTCAACCCAGGCCGCAATAGATC AAATTACAGGCAAGCTGAACCGACTGGTCGAAAAAACCAACACAGAATTCGAGTCCATAGA ATCCGAATTTTCTGAAATAGAACACCAGATTGGGAACGTTATCAATTGGACTAAAGATTCC ATCACCGATATCTGGACATATCAGGCCGAACTGCTTGTGGCCATGGAAAACCAGCATACCA TCGATATGGCTGACTCCGAAATGTTGAATTTGTATGAAAGGGTACGCAAGCAGCTGAGGCA GAACGCTGAGGAGGACGGTAAGGGATGTTTTGAGATCTACCATGCATGCGATGACAGCTGT ATGGAGTCAATACGCAACAACACTTATGACCACTCCCAATATCGGGAGGAAGCACTTCTCA ATCGCTTGAATATTAATCCCGTCACTCTGTCTAGTGGTTATAAGGACATTATTTTGTGGTT CAGCTTTGGAGCCTCCTGTTTCGTTCTACTGGCCGTTGTGATGGGACTATTCTTTTTCTGC CTCAAAAACGGCAACATGCGGTGCACCATCTGTATT 827 ATGTACAAAATAATTGTTATCATAGCCCTCCTGGGTGCCGTCAAAGGGCTGGATAAAATAT GCTTAGGGCACCACGCGGTTGCTAACGGCACCATCGTCAAAACCCTCACAAACGAACAGGA GGAAGTCACCAACGCAACAGAAACAGTCGAATCAACGGGCATCAATAGACTGTGTATGAAA GGGCGCAAGCACAAGGACTTGGGAAACTGCCACCCGATTGGTATGCTAATTGGAACCCCAG CCTGTGACCTACACCTGACCGGGACTTGGGATACTCTTATTGAGCGCGAAAACGCTATTGC GTATTGTTACCCTGGGGCTACCGTCAACGTTGAGGCACTGAGACAGAAAATAATGGAATCA GGTGGCATAGACAAAATTTCTACCGGCTTCACCTACGGGAGCAGCATAAACTCCGCTGGCA CTACACGCGCCTGTATGAGGAATGGCGGCAACTCCTTCTACGCCGAGCTGAAGTGGCTGGT TAGTAAGTCCAAGGGACAGAACTTCCCACAGACCACCAACACTTACCGCAACACCGATACA GCCGAGCACCTGATTATGTGGGGAATACACCACCCAAGCTCTACCCAGGAAAAAAACGACT TGTACGGCACTCAAAGTCTGTCCATCTCCGTTGGGTCGTCCACTTACCGCAATAATTTCGT CCCCGTGGTTGGAGCCCGCCCTCAGGTGAACGGCCAAAGCGGGCGCATCGATTTCCATTGG ACCCTCGTTCAGCCTGGCGACAACATTACCTTTAGTCACAATGGCGGTCTGATTGCCCCTT CACGCGTGTCCAAGTTGATTGGACGGGGATTGGGCATCCAGTCGGACGCACCCATCGATAA CAATTGTGAGAGTAAATGTTTCTGGCGGGGTGGCTCCATTAATACCCGACTGCCATTCCAA AACCTCTCTCCTCGTACGGTGGGTCAGTGTCCCAAGTATGTGAACAGAAGATCTCTGATGT TAGCAACCGGTATGAGAAACGTCCCGGAGCTGATCCAGGGCAGAGGCCTGTTCGGAGCCAT TGCGGGGTTTCTTGAAAACGGATGGGAGGGCATGGTGGACGGATGGTATGGGTTTCGACAT CAAAATGCCCAGGGGACCGGGCAGGCAGCTGACTACAAATCTACCCAGGCGGCAATAGATC AGATCACTGGAAAGTTAAACAGACTCGTGGAGAAAACTAACACTGAGTTCGAATCTATCGA GTCAGAGTTTTCAGAAATTGAACATCAGATCGGAAACGTTATCAATTGGACGAAAGATAGT ATCACAGACATTTGGACCTATCAAGCTGAATTGCTTGTGGCCATGGAAAACCAACATACCA TCGACATGGCTGACTCGGAAATGTTGAATTTGTACGAGCGGGTGAGGAAGCAACTGAGGCA AAATGCCGAGGAGGACGGCAAAGGCTGCTTTGAGATCTACCACGCATGCGATGACTCTTGT ATGGAAAGTATTCGGAATAATACTTATGACCATTCCCAGTATCGTGAGGAAGCACTGCTCA ACCGCCTAAATATTAATCCCGTGACCCTGTCATCAGGGTATAAGGACATTATCCTTTGGTT TTCCTTCGGCGCTAGCTGTTTCGTGCTGCTAGCGGTAGTGATGGGCCTTTTCTTCTTTTGT TTGAAGAATGGCAATATGCGATGCACAATCTGCATA 828 ATGTATAAGATCGTGGTCATCATAGCCCTGCTCGGAGCCGTTAAGGGTCTTGACAAGATTT GTCTTGGTCATCATGCTGTTGCTAACGGAACCATCGTGAAAACTCTGACAAACGAGCAGGA GGAAGTGACAAACGCCACGGAGACAGTGGAATCTACTGGAATCAACCGCTTATGCATGAAA GGCAGGAAACACAAAGACCTGGGGAATTGCCACCCAATTGGAATGCTGATCGGCACACCTG CCTGCGACCTGCATCTCACAGGGATGTGGGATACACTGATCGAAAGAGAGAATGCTATCGC ATACTGCTACCCAGGGGCTACTGTCAATGTGGAGGCCCTTCGACAGAAGATTATGGAATCC GGAGGTATCAACAAAATTAGCACTGGCTTCACCTACGGGTCTTCCATCAATTCTGCCGGCA CGACCAGAGCATGTATGAGAAATGGGGGCAACAGTTTTTACGCCGAGTTGAAGTGGCTGGT GAGTAAGAGCAAAGGACAGAACTTCCCGCAGACCACCAACACATACAGGAATACGGATACC GCCGAGCACTTAATCATGTGGGGAATTCACCACCCCAGTTCGACACAGGAGAAGAACGATC TCTATGGCACTCAGTCTCTGTCTATTTCTGTGGGATCATCAACATATCGCAATAACTTTGT ACCTGTTGTGGGGGCTAGGCCTCAGGTGAACGGCCAATCCGGACGAATCGACTTCCACTGG ACTCTGGTTCAACCAGGTGATAATATTACTTTCTCACACAACGGCGGACTGATTGCACCTA GCCGAGTGAGTAAGCTCATTGGTAGAGGACTGGGGATTCAGTCCGATGCCCCTATAGACAA TAACTGCGAAAGCAAATGCTTCTGGCGCGGCGGAAGCATAAATACAAGATTGCCATTTCAG AACCTGAGTCCTCGGACCGTTGGACAGTGTCCTAAATACGTGAACAGAAGAAGCCTGATGC TTGCCACTGGCATGCGGAATGTGCCCGAGCTCATTCAGGGACGGGGCCTATTCGGCGCAAT CGCCGGATTTCTGGAGAATGGTTGGGAAGGGATGGTCGATGGCTGGTACGGCTTTAGACAC CAGAATGCACAGGGGACAGGGCAGGCGGCCGATTACAAATCCACTCAGGCTGCTATCGACC AGATCACCGGCAAGTTAAATAGGTTGGTCGAGAAGACGAACACCGAATTCGAATCTATCGA GTCAGAGTTTAGCGAGATTGAGCATCAGATAGGTAATGTGATTAACTGGACTAAGGACAGC ATCACTGATATCTGGACTTACCAGGCAGAGCTCCTGGTTGCCATGGAGAACCAGCACACAA TAGACATGGCCGACAGTGAAATGCTAAACCTGTACGAACGCGTGCGCAAGCAGCTCCGGCA GAACGCAGAAGAAGATGGCAAGGGGTGTTTTGAGATATATCATGCATGCGATGACTCCTGT ATGGAGAGTATCCGTAACAACACTTACGATCACTCCCAGTACCGTGAGGAGGCTCTGCTGA ACAGACTGAACATCAACCCCGTAACTTTAAGTAGTGGATATAAGGATATCATTCTTTGGTT TAGCTTCGGAGCAAGCTGTTTCGTCCTTCTCGCAGTGGTTATGGGCCTGTTCTTTTTTTGC CTAAAGAATGGGAATATGCGGTGCACAATATGTATT 829 ATGTATAAGATCGTGGTGATTATTGCCCTGCTGGGCGCTGTGAAGGGCTTAGACAAGATTT GCTTAGGTCACCATGCAGTGGCAAATGGAACAATTGTCAAGACATTGACCAATGAACAGGA GGAGGTAACCAACGCTACAGAAACCGTTGAGTCCACCGGTATTAACCGGCTTTGCATGAAG GGTCGCAAGCACAAGGATCTGGGCAATTGCCACCCCATCGGTATGCTCATTGGAACTCCCG CATGTGATCTGCATCTGACAGGGATGTGGGATACGTTGATAGAGCGTGAGAACGCCATCGC CTACTGTTACCCAGGTGCCACAGTGAACGTGGAAGCCCTGCGTCAAAAGATCATGGAATCC GGAGGGATCAATAAAATTAGTACAGGCTTCACGTATGGCTCTTCCATCAACTCTGCTGGGA CTACTCGTGCGTGCATGCGGAATGGAGGCAATTCATTTTACGCGGAACTAAAATGGCTTGT GAGCAAAAGCAAAGGACAAAACTTCCCGCAGACGACCAACACGTATCGGAACACCGACACC GCCGAACATCTAATCATGTGGGGCATCCATCATCCCTCATCCACCCAGGAAAAAAATGACT TATACGGAACACAGTCATTGAGCATTTCCGTAGGATCAAGTACATACCGAAATAATTTCGT GCCTGTGGTGGGTGCGGGCCCCCAAGTTAATGGCCAATCAGGCCGTATTGACTTTCATTGG ACCCTCGTTCAGCCTGGCGACAACATCACCTTCTCCCATAACGGGGGACTCATCGCCCCAT CAAGAGTGTCGAAGCTGATCGGCCGAGGACTCGGGATACAGTCTGACGCCCCCATCGACAA TAATTGTGAATCCAAGTGCTTTTGGAGAGGAGGGTCAATCAACACCCGCCTACCTTTTCAG AATCTTTCACCCAGGACCGTTGGGCAGTGTCCCAAATACGTGAACCGGAGATCTCTCATGC TTGCAACCGGGATGAGAAACGTGCCAGAGCTCATCCAGGGGCGCGGCCTATTTGGGGCCAT AGCCGGTTTTCTGGAGAACGGATGGGAGGGAATGGTTGATGGCTGGTACGGCTTCAGGCAC CAGAACGCACAGGGCACCGGGCAAGCCGCAGACTACAAATCAACTCAGGCGGCTATCGATC AGATCACAGGTAAATTAAACCGACTCGTCGAAAAGACAAATACCGAGTTTGAGTCTATCGA ATCCGAGTTTTCTGAAATTGAGCATCAAATCGGCAACGTGATTAACTGGACTAAGGACTCC ATCACCGATATTTGGACTTATCAAGCAGAACTACTGGTCGCCATGGAAAATCAACATACTA TCGATATGGCAGATAGCGAAATGCTTAACCTCTACGAAAGAGTGCGAAAGCAGCTACGCCA AAATGCCGAGGAAGACGGGAAGGGCTGCTTCGAGATTTACCATGCGTGTGATGATTCCTGC ATGGAAAGTATTAGGAACAATACTTATGATCACAGCCAGTATCGTGAGGAAGCTCTGCTTA ACAGACTTAACATCAATCCAGTGACACTCAGCAGTGGGTACAAAGACATCATCCTCTGGTT CAGCTTTGGAGCTTCTTGCTTCGTTTTGCTTGCTGTAGTCATGGGACTGTTTTTTTTTTGT CTGAAGAACGGTAATATGCGATGCACTATTTGTATA 830 ATGTATAAGATCGTGGTCATCATCGCTTTGCTGGGGGCTGTTAAGGGGCTCGACAAGATTT GTTTGGGCCACCACGCCGTGGCCAACGGGACCATTGTGAAGACGCTGACAAATGAACAAGA AGAAGTCACAAATGCCACAGAGACTGTTGAATCCACTGGCATTAATAGACTCTGCATGAAA GGCAGGAAACACAAAGATCTGGGCAACTGTCACCCTATCGGAATGCTGATTGGCACTCCCG CTTGTGATCTCCATCTTACAGGTATGTGGGATACCCTTATTGAGCGAGAAAATGCCATCGC CTACTGTTATCCAGGTGCTACTGTGAACGTGGAGGCCTTGAGGCAGAAGATTATGGAGTCA GGAGGCATCAATAAGATTTCCACCGGGTTTACATACGGCTCATCCATCAACTCCGCCGGCA CGACTCGAGCTTGCATGAGAAACGGTGGCAACTCCTTTTATGCGGAGCTAAAGTGGCTGGT CAGCAAGTCAAAAGGTCAGAACTTCCCCCAGACTACGAACACCTATCGGAATACAGACACC GCTGAGCATTTGATCATGTGGGGAATCCACCATCCTAGCTCCACCCAGGAGAAGAATGACC TGTATGGAACACAATCTCTTTCTATCTCCGTGGGCTCTTCTACCTACCGTAACAATTTCGT TCCCGTTGTGGGGGCTCGGCCTCAGGTGAATGGTCAATCCGGAAGAATCGACTTTCACTGG ACATTAGTACAGCCCGGCGACAACATTACATTTAGTCATAATGGGGGGCTGATCGCGCCTA GTCGGGTCTCAAAGTTGATCGGGAGAGGCCTCGGAATCCAGAGCGATGCACCTATCGATAA CAACTGTGAAAGCAAGTGCTTCTGGCGCGGCGGTTCTATTAATACCAGATTGCCCTTCCAG AACCTGTCTCCCCGAACAGTCGGGCAGTGCCCCAAATACGTGAACAGGAGATCTCTGATGC TGGCCACAGGGATGCGCAACGTGCCAGAGCTGATCCAGGGAAGGGGTCTCTTCGGGGCCAT TGCCGGCTTTCTGGAAAATGGCTGGGAAGGGATGGTGGACGGGTGGTATGGCTTCAGGCAC CAAAACGCGCAAGGCACTGGCCAGGCGGCGGATTACAAGAGCACGCAAGCTGCTATAGACC AGATCACGGGGAAGCTGAACAGACTCGTGGAAAAGACTAATACTGAATTTGAATCGATCGA GTCTGAGTTCTCCGAAATCGAGCATCAGATCGGGAATGTCATAAATTGGACCAAGGATTCC ATTACAGATATTTGGACCTATCAGGCCGAACTGCTGGTGGCCATGGAGAATCAGCACACTA TTGATATGGCCGACAGTGAGATGCTGAACCTGTATGAGCGTGTTAGGAAGCAACTTCGACA GAACGCAGAAGAAGATGGTAAGGGATGTTTCGAGATTTACCATGCCTGTGACGACAGTTGT ATGGAGAGCATTAGGAATAACACTTATGACCATAGCCAATACCGGGAAGAAGCTTTGTTAA ATCGCCTGAATATCAATCCCGTCACGTTATCGTCGGGGTATAAGGATATTATTCTGTGGTT CAGCTTCGGAGCGTCCTGCTTTGTTCTGTTGGCCGTGGTAATGGGGCTGTTTTTCTTTTGT CTTAAGAACGGGAACATGCGCTGCACAATCTGCATC 831 ATGTACAAGATTGTGGTTATCATCGCACTGTTAGGAGCCGTGAAGGGGTTGGACAAGATCT GTCTGGGGCATCATGCCGTTGCTAATGGAACAATCGTGAAGACGCTCACCAATGAACAAGA AGAAGTCACAAACGCCACCGAAACCGTGGAGAGCACCGGAATTAACAGACTTTGTATGAAG GGACGCAAACACAAGGATCTGGGGAACTGCCACCCAATCGGCATGCTGATAGGAACCCCTG CCTGTGATCTGCACTTAACTGGCATGTGGGACACACTTATAGAGCGCGAGAACGCGATCGC GTACTGCTACCCCGGAGCAACCGTTAACGTCGAAGCTTTGAGGCAGAAAATTATGGAAAGC GGCGGCATAAATAAAATTTCTACTGGCTTTACGTACGGCAGCTCTATAAACAGTGCTGGCA CCACTCGTGCCTGTATGCGGAACGGCGGCAATTCCTTTTACGCCGAATTAAAATGGCTTGT TAGCAAGTCAAAGGGCCAGAACTTTCCGCAGACGACTAATACATACCGAAACACCGACACC GCTGAACATCTGATTATGTGGGGTATACATCATCCAAGTTCCACCCAAGAAAAAAATGACT TGTATGGGACCCAGAGCCTAAGCATCTCCGTGGGGAGTTCTACTTACCGAAACAACTTCGT ACCTGTGGTGGGGGCCCGACCACAGGTAAATGGACAGTCGGGCCGGATTGATTTCCACTGG ACCTTGGTGCAGCCGGGAGATAACATAACATTCTCTCATAACGGAGGTCTCATAGCCCCAA GTCGTGTGTCAAAGCTCATCGGTAGAGGCCTGGGCATTCAGTCAGACGCACCCATTGATAA TAACTGTGAGTCTAAATGCTTTTGGCGCGGCGGGAGTATCAATACTAGACTGCCTTTTCAG AACCTCAGCCCAAGGACCGTGGGGCAGTGTCCCAAGTATGTAAATCGGCGAAGCTTAATGC TGGCTACTGGTATGCGGAATGTGCCTGAACTCATTCAGGGACGGGGCCTCTTCGGAGCAAT AGCTGGTTTCCTGGAGAACGGCTGGGAAGGCATGGTGGATGGTTGGTACGGTTTTAGACAC CAAAATGCCCAGGGAACGGGACAGGCTGCCGACTATAAGTCAACTCAAGCCGCGATCGACC AGATCACTGGTAAATTAAACCGACTCGTCGAAAAGACAAACACGGAGTTCGAGTCTATCGA AAGTGAGTTCTCAGAGATTGAACACCAAATCGGGAATGTGATTAACTGGACAAAGGACTCG ATAACCGATATCTGGACCTACCAGGCAGAACTTCTGGTGGCCATGGAAAACCAGCACACTA TTGACATGGCCGACTCAGAGATGCTGAATCTGTACGAGAGAGTGAGGAAGCAGCTCCGCCA GAATGCGGAGGAGGATGGTAAAGGCTGCTTCGAAATCTACCACGCTTGCGATGACTCCTGC ATGGAATCAATCCGAAATAATACATATGACCACTCACAGTACAGAGAAGAAGCCCTTCTGA ACCGCCTGAACATCAACCCCGTGACGCTGAGTTCAGGATATAAGGATATCATTCTCTGGTT CTCCTTTGGGGCGAGTTGCTTCGTGCTGCTTGCGGTAGTCATGGGACTCTTTTTTTTTTGT CTTAAGAACGGTAATATGCGGTGCACTATTTGTATC 832 ATGTACAAGATCGTGGTAATTATCGCCCTGCTCGGAGCTGTGAAAGGATTAGACAAAATTT GCCTCGGCCACCATGCTGTAGCTAATGGTACAATAGTCAAAACCCTAACTAATGAACAGGA AGAGGTGACTAATGCAACGGAAACTGTCGAGAGTACCGGCATTAACCGCCTGTGTATGAAA GGGAGAAAGCACAAGGACTTAGGCAATTGTCATCCAATCGGGATGCTAATTGGCACTCCAG CCTGTGATCTGCATCTGACCGGAATGTGGGACACCTTAATTGAGAGGGAAAACGCCATAGC CTATTGCTATCCTGGGGCAACTGTTAATGTGGAAGCTCTCCGGCAAAAAATCATGGAATCT GGAGGCATTAATAAGATCTCCACGGGCTTCACATATGGGTCCTCTATCAATTCCGCCGGGA CCACGCGCGCATGCATGAGAAACGGAGGGAATTCTTTCTACGCGGAACTTAAGTGGCTGGT CAGTAAGTCTAAAGGGCAGAATTTTCCTCAGACCACTAATACCTACAGAAATACGGATACA GCTGAGCACCTCATTATGTGGGGAATACACCACCCTTCAAGCACACAGGAAAAAAACGATC TCTACGGGACCCAGAGCCTGTCCATTAGTGTCGGATCTAGCACATACCGGAACAATTTCGT ACCCGTTGTGGGAGCACGCCCACAGGTGAATGGGCAGTCAGGCAGAATCGATTTCCATTGG ACTCTCGTGCAGCCCGGCGATAATATAACCTTCAGTCATAATGGCGGATTGATCGCCCCCT CGCGTGTTTCAAAATTAATCGGGAGGGGGCTCGGGATACAAAGCGACGCTCCTATCGACAA CAACTGTGAGTCCAAGTGTTTTTGGCGCGGCGGGAGCATTAATACCCGTCTCCCGTTCCAG AACCTGTCTCCCCGGACAGTAGGACAGTGTCCGAAGTATGTCAATCGTAGAAGTCTTATGC TGGCGACGGGAATGCGGAACGTGCCCGAGCTGATTCAAGGCCGGGGTCTGTTCGGAGCAAT AGCTGGTTTCCTGGAGAATGGTTGGGAGGGCATGGTTGACGGCTGGTATGGGTTCAGACAT CAGAACGCACAGGGAACCGGCCAGGCTGCTGACTATAAATCCACTCAGGCAGCCATAGATC AGATCACCGGGAAGCTAAACCGGCTGGTTGAGAAAACTAATACGGAGTTCGAGTCTATCGA GTCCGAGTTTAGCGAAATAGAGCATCAGATAGGGAACGTGATAAATTGGACGAAAGACTCT ATTACCGACATCTGGACCTACCAGGCGGAACTGCTGGTGGCTATGGAGAATCAGCACACCA TCGACATGGCTGATAGCGAAATGTTGAATCTGTACGAGCGGGTCAGAAAACAGTTAAGACA GAACGCAGAGGAAGATGGAAAGGGCTGCTTCGAAATATATCACGCATGTGATGATTCCTGC ATGGAGTCTATTAGAAACAACACTTATGACCATTCGCAGTACCGCGAAGAAGCGCTGCTAA ACAGACTCAACATCAATCCTGTGACCTTGAGTAGCGGATACAAGGACATTATACTGTGGTT CTCCTTTGGTGCCTCCTGTTTTGTCTTGCTTGCCGTAGTTATGGGCCTGTTCTTTTTCTGC TTGAAGAACGGGAACATGCGCTGCACAATTTGTATC 833 ATGTATAAAGTGGTGGTGATTATCGCTTTACTGGGAGCTGTAAAGGGGCTGGATAAGATTT GTCTGGGACATCACGCAGTCGCGAACGGCACCATTGTGAAAACACTTACTAATGAACAGGA GGAGGTGACCAACGCCACCGAAACCGTCGAGTCAACAGGTATAAACAGATTGTGCATGAAG GGCCGAAAGCACAAGGACCTGGGAAATTGTCATCCAATTGGAATGTTGATCGGCACTCCAG CCTGCGATCTTCATCTTACCGGAACATGGGACACGCTTATTGAACGGGAAAATGCGATCGC ATATTGCTACCCCGGGGCCACAGTGAATGTGGAGGCACTGAGACAGAAAATCATGGAAAGT GGCGGGATCGACAAGATTAGTACTGGCTTTACATACGGGAGCAGCATCAACTCCGCCGGGA CCACCCGAGCCTGCATGAGGAACGGGGGCAACAGTTTTTATGCTGAGCTGAAGTGGCTCGT GTCAAAAAATAAGGGCCAGAATTTCCCTCAAACAACGAATACATATCGCAACACAGATACA GCGGAACACTTAATCATGTGGGGCATTCACCACCCTAGCTCCATTCAAGAAAAGAACGATC TCTACGGAACACAATCGTTGAGCATCTCAGTGGGGTCTTCCACCTATAGAAACAACTTTGT ACCTGTGGTCGGCGCAAGACCTCAAGTCAATGGACAAAGCGGCAGAATCGACTTCCACTGG ACTCTGGTGCAGCCAGGCGATAATATAACCTTCTCTCACAACGGCGGCTTGATCGCTCCCA GCCGGGTATCTAAGTTAATCGGCCGTGGTCTCGGAATCCAGAGCGATGCACCGATTGACAA TAACTGTGAAAGTAAATGTTTCTGGCGTGGCGGCTCTATAAACACTAGACTCCCCTTCCAG AACTTGAGTCCTAGAACAGTGGGGCAGTGCCCGAAATACGTCAACCGGAGATCGTTGATGC TCGCAACTGGCATGAGGAACGTCCCCGAGTTAATACAGGGACGGGGACTATTCGGCGCCAT AGCCGGGTTCCTCGAGAACGGATGGGAGGGTATGGTTGATGGTTGGTACGGCTTTCGACAT CAAAACGCACAAGGTACAGGGCAGGCTGCCGATTACAAGAGCACTCAGGCCGCCATCGACC AGATCACTGGGAAACTCAACAGGTTAGTGGAGAAAACCAATACCGAATTTGAATCCATCGA GAGCGAATTCTCAGAGATTGAGCATCAGATAGGAAATGTGATAAACTGGACCATGGATAGT ATTACAGACATTTGGACGTACCAAGCAGAGCTGCTTGTCGCGATGGAGAATCAACACACCA TCGACATGGCGGACTCCGAAATGCTGAATCTGTATGAGAGGGTTCGGAAACAGCTTAGACA AAATGCAGAGGAGGATGGCAAGGGCTGCTTTGAGATCTACCACGCATGTGATGACTCCTGT ATGGAATCCATCCGGAACAACACGTATGACCACTCTCAGTACAGAGAAGAGGCTCTCCTGA ATCGCCTTAATATTAACCCTGTGACACTGTCCTCCGGCTATAAGGATATCATCCTGTGGTT TAGCTTTGGAGCAAGCTGCTTCGTGTTGCTGGCCGTAGTTATGGGCCTGGTCTTCTTCTGT CTTAAGAACGGAAACATGCGGTGCACAATCTGTATT 834 ATGTATAAGGTCGTCGTTATTATAGCGCTGCTTGGAGCTGTCAAAGGTTTGGATAAAATCT GTCTGGGCCATCACGCAGTCGCCAACGGTACCATTGTGAAAACGCTCACAAACGAACAGGA AGAGGTCACGAACGCCACAGAGACTGTGGAGTCTACAGGGATTAACCGCCTGTGCATGAAA GGCCGGAAACATAAGGACCTTGGCAACTGCCATCCAATCGGCATGCTGATTGGCACTCCGG CCTGTGATCTGCATTTGACCGGCACATGGGATACCCTGATCGAAAGGGAGAATGCCATCGC TTACTGTTATCCCGGCGCAACTGTGAATGTGGAGGCACTGAGACAGAAGATCATGGAGTCT GGGGGGATCGATAAAATTAGTACCGGGTTTACTTACGGCAGTTCGATTAATAGCGCGGGAA CAACGAGGGCGTGTATGAGGAATGGAGGAAACTCCTTCTATGCCGAGCTCAAGTGGCTGGT GAGCAAGAACAAGGGGCAAAACTTTCCCCAAACAACTAACACATACCGGAATACAGATACT GCTGAACATCTGATAATGTGGGGAATCCACCATCCTTCTTCAATTCAGGAGAAAAACGATC TTTACGGAACTCAAAGTTTAAGCATAAGTGTGGGGTCATCTACGTATAGAAACAACTTTGT GCCCGTGGTTGGCGCAAGGCCGCAGGTGAATGGTCAATCTGGGAGGATAGATTTCCACTGG ACATTGGTGCAGCCGGGTGATAATATCACCTTTTCCCATAATGGGGGATTGATTGCCCCCT CCCGGGTGTCGAAACTTATTGGCCGCGGGCTAGGTATTCAGAGTGACGCCCCCATTGATAA TAATTGTGAGTCTAAATGTTTTTGGCGGGGTGGCAGCATTAATACACGTCTGCCATTCCAG AACCTGTCCCCCAGGACTGTCGGGCAATGCCCCAAATACGTGAATAGACGGTCTCTGATGC TGGCCACTGGGATGCGCAATGTACCCGAGCTTATCCAGGGACGGGGCCTTTTTGGGGCCAT CGCCGGTTTCCTGGAGAACGGGTGGGAAGGCATGGTTGATGGCTGGTATGGGTTTAGACAC CAGAATGCTCAAGGGACTGGGCAGGCGGCCGATTATAAGAGTACACAGGCGGCCATCGACC AGATCACAGGCAAGCTCAACCGTCTGGTGGAGAAAACAAATACAGAATTCGAAAGCATAGA GAGTGAATTTTCTGAGATTGAGCACCAGATTGGTAATGTCATCAATTGGACAATGGATTCC ATCACTGACATCTGGACATACCAAGCCGAGCTATTGGTGGCGATGGAGAATCAGCATACAA TAGATATGGCCGACTCTGAAATGCTGAACTTATATGAGAGAGTGCGTAAACAGTTGAGGCA GAATGCTGAAGAAGACGGTAAGGGATGTTTTGAGATATATCATGCCTGTGATGACAGTTGC ATGGAATCCATCAGAAATAACACTTACGACCACAGCCAGTACAGAGAGGAAGCCCTACTGA ACAGGCTCAATATCAATCCAGTGACTCTATCCAGCGGCTACAAGGACATTATCTTATGGTT TTCTTTTGGTGCTTCATGTTTTGTGCTCCTCGCCGTGGTCATGGGGCTCGTCTTCTTCTGT TTAAAGAATGGGAATATGCGGTGCACAATATGTATC 835 ATGTACAAAATAGTAGTAATCATTGCTTTGCTTGGCGCGGTGAAAGGCTTGGATAAGATTT GCCTGGGACACCATGCTGTCGCGAATGGAACCATAGTTAAGACTTTGACTAATGAGCAAGA GGAGGTGACCAACGCCACCGAAACGGTGGAGTCCACAGGCATCAACAGGCTCTGTATGAAA GGACGGAAGCATAAGGACCTGGGGAACTGTCATCCAATTGGAATGCTGATCGGGACGCCCG CGTGTGACCTCCATCTGACAGGGATGTGGGATACTCTTATTGAGAGAGAGAACGCTATCGC CTACTGTTATCCTGGTGCTACAGTGAACGTGGAAGCCCTCAGGCAGAAGATTATGGAGAGC GGTGGGATCAACAAGATTAGTACAGGGTTTACCTATGGGTCATCCATAAACAGTGCGGGCA CTACCCGAGCGTGCATGCGCAATGGGGGCAATTCGTTCTATGCCGAACTGAAGTGGTTAGT CTCTAAGTCTAAAGGTCAGAATTTTCCTCAGACAACTAACACATACCGGAATACCGATACC GCTGAACACCTGATCATGTGGGGAATACATCACCCTAGTAGTACACAAGAGAAAAATGACC TATATGGGACACAGAGCCTGTCAATTAGCGTGGGTAGTTCCACATATAGAAACAACTTTGT TCCTGTCGTGGGTGCCCGGCCTCAGGTAAATGGGCAGAGCGGACGGATAGATTTTCATTGG ACTTTGGTCCAGCCCGGGGATAACATTACCTTCTCTCATAACGGGGGGCTGATCGCTCCAA GCCGGGTGTCTAAGCTCATAGGCAGAGGCCTGGGTATCCAATCGGACGCCCCCATCGATAA CAACTGTGAAAGTAAATGCTTTTGGAGGGGCGGCAGTATTAATACGCGGCTACCGTTTCAG AATCTGTCTCCACGCACAGTAGGGCAGTGTCCAAAGTACGTCAACCGCAGATCCCTCATGC TGGCCACGGGGATGAGGAACGTGCCCGAGCTGATCCAGGGGAGGGGCCTATTTGGGGCTAT CGCCGGCTTCCTGGAGAATGGTTGGGAGGGAATGGTCGATGGCTGGTACGGCTTTCGCCAT CAGAACGCCCAAGGAACTGGACAAGCTGCCGACTACAAAAGCACGCAAGCCGCCATCGATC AAATTACCGGAAAGCTGAATCGGCTAGTGGAGAAGACCAACACCGAATTTGAGTCTATAGA GTCAGAGTTTAGCGAAATCGAGCATCAGATTGGCAACGTCATTAATTGGACCAAGGACAGC ATAACCGACATATGGACATACCAAGCCGAACTCCTGGTAGCTATGGAAAATCAGCATACCA TCGATATGGCAGATTCCGAAATGCTGAACCTGTATGAAAGAGTGAGGAAGCAACTGCGTCA GAATGCCGAGGAAGACGGCAAGGGGTGCTTTGAGATCTACCACGCATGTGATGATTCTTGC ATGGAGAGCATCAGGAATAATACATACGACCACAGCCAGTACCGGGAAGAAGCCCTATTGA ACAGGCTTAACATCAATCCCGTCACTCTATCCAGCGGCTATAAAGATATAATCTTATGGTT TTCCTTTGGCGCGTCTTGCTTTGTGCTCCTGGCGGTGGTGATGGGCTTATTCTTCTTTTGT CTCAAGAATGGCAACATGAGGTGCACAATCTGCATT 836 ATGTACAAGATAGTGGTCATCATCGCACTCCTGGGCGCCGTGAAGGGCCTGGATAAAATTT GCCTGGGGCACCATGCCGTCGTGAACGGCACGATCGTCAAGACTCTCACTAATGAGCAGGA GGAAGTCACTAATGCTACGGAGACAGTTGAGTCGACCGGATTGAATAGATTGTGCATGAAG GGACGTAACCACAAGGACCTCGGGAACTGCCACCCAATTGGCATGTTGATCGGAACACCCG CCTGCGATCTCCATCTGACCGGTACGTGGGATACACTTATCGAGAGGGAAAACGCAATCGC CTATTGCTATCCCGGTGCAACCGTTAACGAAGAAGCTCTGAGGCAGAAAATCATGGAGTCT GGTGGGATTAACAAGATTAGTACAGGGTTTACATACGGAAGCTCCATCAACAGTGCAGGCA CTACCCGTGCCTGCATGAGAAACGGAGGCAACTCTTTTTACGCTGAACTTAAATGGTTAGT AAGCAAGAGTAAAGGCCAGAATTTTCCACAGACGACAAACACATACAGAAACACCGACACA GCCGAACACCTGATCATGTGGGGCATCCACCACCCATCCAGCACCCAGGAGAAGAACGATC TATATGGAACTCAGAGCCTGTCTATTAGCGTAGGCAGTTCAACCTACCAGAATAACTTCGT GCCAGTGGTGGGAGCTCGGCCTCAGGTTAATGGACAGAGCGGCAGAATCGACTTCCACTGG ACTCTCGTGCAACCCGGCGATAACATCACTTTTTCGCATAATGGAGGCTTAATCGCACCCT CCCGAGTCAGCAAGCTCATCGGAAGGGGATTAGGCATACAGAGTGATGCACCCATCGATAA CAACTGCGAAAGTAAGTGCTTCTGGCGAGGGGGTTCCATTAATACTAGATTACCATTTCAA AATCTGAGTCCAAGAACCGTTGGTCAGTGCCCGAAGTATGTCAATAAGCGTTCTCTGATGT TGGCAACTGGGATGAGGAATGTGCCAGAACTGATGCAAGGGCGAGGCCTCTTTGGTGCAAT CGCTGGCTTTATAGAGAACGGGTGGGAAGGGATGGTGGATGGCTGGTATGGGTTCCGCCAT CAGAATGCACAAGGCACCGGTCAGGCCGCCGACTACAAGTCAACCCAGGCGGCTATCGATC AAATCACGGGGAAACTGAACAGGTTAATCGAAAAAACAAACACAGAGTTCGAGTCAATCGA ATGTATAAAATTATTGTGATCATTGCACTGCTGGGGGCCGTTAAGGGTCTGGACAAAATTT GTCTAGGACACCACGCTGTGGCAAACGGTACTATCGTGAAAACATTGACCAACGAACAGGA GGAGGTTACCAACGCCACCGAGACAGTCGAAAGTACCGGAATTAATCGCCTCTGCATGAAA GGCCGAAAGCATAAGGACCTGGGGAATTGCCATCCCATCGGAATGCTGATCGGCACCCCAG CCTGTGACTTGCATCTTACAGGAACCTGGGACACACTAATCGAAAGGGAAAACGCCATTGC TTACTGTTACCCGGGCGCTACAGTTAACGTGGAGGCCCTTAGGCAGAAAATCATGGAGTCC GGCGGGATCGACAAGATCAGTACCGGCTTCACCTATGGGTCAAGCATCAATTCTGCGGGCA CTACGAGGGCATGCATGAGGAACGGAGGCAACTCATTCTATGCGGAATTGAAGTGGCTGGT CTCCAAGTCCAAAGGGCAGAACTTCCCTCAAACTACTAACACCTACCGGAATACAGACACA GCGGAACACCTCATTATGTGGGGCATCCACCACCCTTCTAGTACTCAAGAGAAGAATGATC TCTACGGCACTCAGTCCCTGAGTATTAGTGTCGGCTCAAGCACCTATAGAAACAATTTCGT GCCCGTTGTGGGGGCCCGCCCTCAGGTTAATGGTCAATCAGGGCGAATTGATTTTCACTGG ACCCTGGTCCAGCCCGGGGACAACATAACATTCAGCCATAATGGGGGTCTGATTGCCCCCA GCCGGGTGAGCAAGTTGATAGGGAGGGGACTTGGCATCCAGAGTGACGCCCCTATTGACAA CAACTGCGAAAGCAAATGCTTTTGGCGGGGTGGCTCAATAAACACAAGGCTACCCTTCCAA AATTTGAGTCCAAGGACCGTGGGTCAATGCCCTAAATACGTCAATCGCCGCTCCTTGATGC TCGCCACTGGGATGCGCAACGTGCCTGAGCTTATTCAGGGTCGGGGTCTGTTCGGGGCTAT CGCCGGGTTCCTTGAAAATGGCTGGGAGGGTATGGTAGACGGCTGGTACGGATTTAGACAC CAGAACGCCCAGGGAACGGGCCAGGCGGCAGACTACAAGTCTACCCAAGCTGCAATCGATC AGATCACTGGCAAGTTAAACAGACTGGTGGAAAAGACAAATACCGAATTTGAAAGCATTGA ATCGGAATTCTCAGAGATCGAGCACCAGATTGGAAATGTGATTAATTGGACGAAAGACAGT ATTACCGACATCTGGACTTATCAGGCAGAACTGCTGGTTGCCATGGAAAACCAGCATACCA TAGATATGGCAGATTCTGAAATGCTCAATCTTTACGAGCGCGTACGGAAACAGTTAAGACA GAACGCAGAGGAGGACGGGAAAGGTTGCTTTGAAATATACCACGCATGTGACGATTCTTGC ATGGAAAGTATCCGCAATAATACGTATGATCACAGTCAATACCGAGAAGAGGCTCTCTTGA ATCGTTTGAATATCAATCCAGTGACCCTGTCCTCCGGATATAAGGATATAATTCTGTGGTT CAGTTTTGGGGCAAGTTGCTTCGTCCTCCTCGCTGTCGTTATGGGACTGTTTTTTTTTTGT CTAAAGAACGGAAACATGCGCTGCACTATATGCATT 844 ATGTATAAAATAGTTGTCATCATTGCACTCTTGGGCGCCGTGAAAGGACTGGATAAAATAT GTCTCGGCCACCATGCAGTTGCAAACGGGACAATTGTGAAAACATTGACCAACGAGCAGGA GGAGGTGACCAATGCTACAGAGACGGTGGAATCTACTGGCATCAACCGATTGTGCATGAAA GGTAGGAAACACAAGGATTTGGGTAATTGCCATCCGATTGGGATGCTTATCGGAACCCCAG CTTGCGATCTGCATTTGACCGGAATGTGGGACACCCTGATTGAGAGGGAAAACGCCATCGC CTACTGCTATCCTGGCGCAACAGTTAACGTGGAGGCACTTCGCCAGAAGATCATGGAAAGC GGGGGGATAAACAAGATCTCTACAGGTTTCACCTATGGTTCTTCCATTAACAGCGCCGGTA CCACACGAGCTTGTATGCGAAATGGGGGCAACTCCTTCTACGCTGAATTAAAATGGCTGGT GTCGAAGTCCAAAGGGCAGAACTTCCCTCAGACAACAAACACCTACCGGAACACAGACACC GCGGAGCACCTGATCATGTGGGGTATACACCACCCCAGCTCTACCCAGGAAAAGAATGATC TCTATGGAACCCAGTCATTAAGTATCAGCGTCGGTTCCTCTACATATCGTAATAATTTCGT GCCTGTGGTTGGCGCCAGGCCACAAGTGAATGGGCAGTCCGGCAGAATTGACTTTCATTGG ACTCTGGTGCAGCCAGGCGACAATATCACATTCTCTCACAACGGGGGACTTATCGCCCCCT CCAGGGTGTCAAAACTCATCGGCCGGGGGCTGGGAATCCAAAGCGATGCTCCCATCGACAA CAATTGCGAATCAAAATGTTTCTGGCGAGGGGGTTCCATAAATACCAGACTGCCATTCCAG AACCTGTCCCCAAGAACAGTGGGCCAATGTCCCAAGTATGTGAACAGAAGGTCTTTGATGC TCGCAACTGGGATGCGAAATGTTCCAGAGCTGATTCAGGGTCGAGGACTTTTTGGAGCCAT CGCTGGCTTCTTAGAGAACGGCTGGGAAGGAATGGTGGACGGCTGGTATGGCTTTAGACAC CAGAACGCCCAGGGTACGGGACAGGCTGCAGATTACAAATCTACACAGGCCGCAATCGACC AGATCACAGGCAAGCTCAATCGGCTTGTGGAGAAGACAAACACAGAGTTTGAGAGCATTGA ATCGGAATTTAGTGAGATTGAGCACCAGATTGGCAATGTGATTAATTGGACTAAAGACTCT ATTACGGATATCTGGACGTATCAGGCAGAGCTGTTGGTGGCAATGGAAAATCAACACACTA TCGACATGGCCGATAGTGAGATGCTCAATCTATATGAGAGGGTTCGCAAGCAGCTGCGTCA AAATGCCGAGGAGGATGGCAAGGGATGTTTCGAGATTTATCACGCCTGCGATGATTCGTGC ATGGAGAGCATTCGCAATAACACGTACGATCACTCTCAGTACAGGGAGGAGGCACTTTTAA ACCGTCTCAACATCAACCCTGTGACCCTGAGCTCTGGCTACAAAGACATCATTTTGTGGTT CTCCTTTGGAGCCAGCTGCTTCGTGCTCCTCGCCGTGGTCATGGGCTTGTTTTTCTTCTGT CTGAAGAATGGAAATATGCGATGCACCATCTGTATT 845 ATGTACAAGGTGGTAGTTATAATCGCACTTCTGGGAGCAGTGAGAGGTCTCGACAAGATTT GCCTCGGGCACCACGCTGTGGCTAATGGCACAATTGTGAAGACCTTGACAAATGAGCAGGA AGAAGTGACAAATGCGACTGAGACTGTCGAGTCCAAGTCTCTGGGCAAGTTGTGCATGAAG GTCTGAGTTTTCTGAAATTGAGCACCAAATCGGGAATGTGATTAACTGGACAAAAGACTCT ATCACAGACATCTGGACCTACCAGGCCGAACTCCTGGTGGCCATGGAGAATCAACACACCA TTGACATGGCGGACTCCGAAATGCTGAATCTGTATGAGAGGGTTAGGAAACAACTTAGGCA GAATGCTGAGGAAGACGGCAAAGGCTGTTTTGAAATTTACCACGCCTGTGATGATAGTTGT ATGGAGAGCATTCGGAACAATACCTACGATCACTCTCAATATCGCGAGGAAGCTCTGCTTA ACAGGCTTAACATTAACCCCGTGACGCTGTCAAGTGGCTACAAAGACATTATTCTCTGGTT CTCCTTCGGTGCATCATGCTTTGTTCTGCTGGCTGTTGTCATGGGCTTAGTGTTCTTCTGC CTCAAGAACGGTAATATGAGATGTACCATCTGCATT 837 ATGTATAAGGTGGTGGTGATCATCGCCCTCTTGGGTGCTGTTAGAGGGCTGGATAAAATCT GTCTAGGACATCATGCCGTGGCAAACGGTACTATCGTAAAAACTCTGACAAATGAGCAGGA GGAGGTGACCAACGCTACTGAGACCGTCGAGTCAAAGAGCCTGGGAAAGTTGTGCATGAAA GGGAGGTCATATAATGACCTGGGGAACTGTCACCCTATAGGTATACTTATTGGCACCCCTG CCTGCGATCTCCATCTCACTGGGACATGGGACACCCTGATTGAACGGGAGAACGCTGTTGC TTATTGCTACCCCGGTGCTACAGTTAATGAGGAGGCGTTGCGTCAGAAGATAATGGAAAGC GGGGGAATCTCGAAGATTAGCACTGGCTTTACCTACGGGACCAGTATTAATAGCGCGGGAA CCACAAAAGCCTGCATGAGAAACGGAGGCAACAGCTTTTACGCCGAATTGAAATGGTTAGT GTCAAAGAACAAAGGACAGAACTTCCCTCAGACCACAAACACGTACAGAAACACCGATACT GCTGAGCACTTGATTATCTGGGGCATTCATCACCCATCTAGCACACAAGAGAAAAATGATC TGTATGGAACCCAGTCACTGAGCATCTCAGTCGGCAGTTCCACTTACCAAAATAATTTTGT TCCTGTGGTGGGAGCACGCCCACAGGTGAATGGACAGTCTGGAAGGATTGATTTTCACTGG ACCCTGTTGCAGCCAGGAGACAATATAACCTTCAGTCATAACGGGGGCCTCATCGCGCCGT CTCGGGTGTCAAAGTTGATTGGAAGAGGACTCGGGATTCAATCCGAAGCCCCCATCGATAA TGGCTGTGAATCTAAATGCTTTTGGAAAGGTGGTTCGATCAATACAAAGCTGCCCTTCCAA AACCTTTCCCCGCGGACAGTTGGACAATGCCCCAAGTACGTGAACAAGCGCAGTCTGATGC TCGCCACCGGGATGAGAAACGTGCCGGAGATTATGCATGGCAGGGGCCTGTTCGGAGCTAT CGCTGGATTCATTGAAAACGGGTGGGAGGGCATGGTTGACGGCTGGTATGGATTCAGGCAT CAGAACGCACAGGGGACAGGCCAGGCAGCTGACTATAAGAGTACCCAGGCCGCTATCGACC AAATAACAGGTAAGCTTAACCGTCTTATCGAAAAAACTAACACAGAGTTCGAATCAATCGA AAGCGAATTCAGTGAGATTGAACACCAGATTGGTAACATAATTAATTGGACAAAAGACTCT ATCACAGATATTTGGACCTACCAGGCAGAACTGCTCGTGGCCATGGAAAACCAGCACACTA TCGATATGGCAGATTCCGAAATGTTAAACCTGTATGAGCGAGTGCGAAAACAACTGCGCCA AAATGCAGAGGAAGACGGGAAAGGCTGTTTTGAAATTTACCATGCGTGCGACGATTCTTGT ATGGAATCCATCAGAAACAACACATATGATCACTCTCAGTATAGAGAAGAGGCTCTTCTGA ATCGCTTGAATATAAACCCTGTGAAGTTAAGTTCAGGGTATAAAGATATCATCCTTTGGTT CTCTTTCGGGGCTTCTTGTCTGATCTTGCTTGCTGTGGTCATGGGTCTCGTGTTTTTTTGT CTGAAAAACGGCAACATGCGATGTACAATTTGTATT 838 ATGTACAAGATTGTAGTCATCATCGCCCTACTGGGTGCAGTCAAGGGACTGGACAAAATAT GCCTGGGCCATCATGCAGTGGCCAACGGGACCATTGTTAAGACACTTACAAATGAGAAAGA AGAGGTTACTAATGCCACCGAAACTGTGGAGTCCACCGGCCTAAACCGACTCTGCATGAAG GGAAGGAAACACAAAGATCTGGGAAACTGCCACCCCATAGGGATGCTCATCGGCTCTCCCG CATGTGACCTGCATCTGACAGGAACCTGGGATACCCTGATCGAGAGAGAAAACGCGATCGC CTATTGTTACCCCGGCGCGACAGTGAATGGTGAGGCTCTGCGCCAAAAAATAATGGAATCA GGAGGAATAGACAAAATTTCAACAGGATTTACATACGAATCCTCCATTAATAGCGCCGGCA CAACTAGAGCTTGTATGCGGAATGGGGGCAATTCCTTTTACGCGGAGCTGAAATGGTTGGT ATCTAAAAGCAAAGGACAGAACTTCCCTCAGACTACCAACACCTATCGAAATACAGACACA GCCGAGCACTTAATTATGTGGGGGATACATCACCCCTCTTCTACACAGGAGAAAAATGACT TATACGGAACCCAATCCTTAAGCATTAGTGTGGGCAGCAGCACATATCGAAACAATTTTGT ACCAGTGGTAGGAGCTCGCCCTCAGGTGAATGGACAGAGCGGCCGGATTGATTTCCACTGG ACACTGGTTCAGCCTGGCGACAATATCACATTCAGCCATAACGGTGGTTTGATTGCTCCTT CCAGAGTCAGTAAATTGATCGGGAGAGGACTGGGGATTCAGTCAGACGCCCCCATTGATAA TAACTGTGAAAGCAAGTGCTTTTGGAGAGGTGGATCCATCAACACACGTCTGCCCTTCCAG AACCTGAGTCCCCGGACAGTCGGTCAGTGTCCGAAGTACGTCAACAAACGGAGTTTAATGC TCGCGACTGGGATGAGGAACGTGCCTGAACTTATGCAAGGCCGGGGCTTATTCGGGGCCAT TGCGGGCTTTCTGGAAAACGGGTGGGAAGGGATGGTTGATGGGTGGTACGGGTTCAGACAC CAGAATGCTCAGGGCACCGGACAAGCCGCAGATTATAAGTCAACCCAGGCCGCAATAGATC AGATTACCGGCAAACTGAACAGGCTCGTCGAGAAAACCAATACTGAGTTTGAATCTATTGA AAGCGAGTTTTCAGAGATTGAACATCAAATCGGCAATGTGATTAATTGGACCAAAGATTCG ATTACAGATATATGGACCTACCAGGCTGAACTTCTTGTCGCCATGGAAAACCAGCATACGA TCGATATGGCCGACAGCGAAATGTTAAACCTATACGAGCGGGTGAGGAAGCAGCTGAGGCA GAACGCAGAAGAGGACGGGAAAGGCTGTTTTGAAATATACCACGCCTGTGATGATTCTTGC ATGGAGTCGATCCGTAACAACACATACGACCATTCTCAATATCGAGAGGAAGCATTATTGA ACAGGTTAAACATCAATCCCGTTACTCTCTCCAGCGGATATAAAGACATTATCCTTTGGTT TTCATTCGGAGCATCCTGTTTTGTCTTACTAGCCGTCGTAATGGGTTTAGTCTTCTTTTGC CTTAAGAACGGGAATATGAGGTGTACCATATGTATT 839 ATGTATAAAATCGTGGTGATCATCGCTCTTCTTGGCGCTGTGAAGGGGCTCGACAAGATCT GCTTAGGTCATCACGCAGTGGCTAATGGTACGATCGTGAAGACACTGACGAATGAACAGGA AGAAGTCACAAATGCCACGGAGACCGTTGAGAGCACTGGCATCAATAGACTGTGCATGAAA GGACGCAAGCACAAGGACCTGGGCAATTGCCATCCTATCGGCATGCTGATTGGAACGCCGG CGTGTGACCTGCATTTGACCGGGATGTGGGATACCCTAATCGAGAGGGAGAACGCAATTGC CTATTGTTACCCCGGCGCAACCGTGAATGTGGAAGCCCTGCGACAAAAGATCATGGAGAGT GGTGGCATTAATAAGATTTCTACCGGGTTCACTTATGGCAGTAGCATCAACTCTGCCGGCA CAACCAGGGCTTGTATGAGGAATGGAGGCAACAGCTTTTATGCTGAACTTAAATGGCTCGT CAGCAAGTCTAAAGGTCAGAACTTCCCTCAGACCACAAATACATACAGAAATACTGACACA GCCGAGCACCTCATCATGTGGGGCATCCATCATCCATCTTCCACCCAAGAGAAAAACGACC TCTACGGGACACAGAGCCTGTCTATAAGCGTGGGCTCTAGCACTTATAGAAATAATTTCGT TCCAGTGGTGGGCGCACGTCCCCAAGTTAACGGCCAGAGCGGAAGGATCGATTTCCATTGG ACTCTGGTGCAGCCTGGGGACAACATTACATTTTCCCACAATGGAGGTCTTATTGCACCCT CACGGGTATCCAAGTTAATCGGCCGCGGACTTGGCATCCAATCAGATGCACCCATCGACAA CAATTGTGAGAGTAAGTGCTTCTGGCGTGGTGGGAGCATCAACACGAGATTACCTTTCCAG AATCTGAGCCCGAGAACAGTAGGGCAATGTCCAAAGTATGTGAACAGGCGCAGCCTCATGC TCGCGACCGGAATGAGAAATGTTCCCGAACTGATACAAGGAAGGGGTTTGTTCGGCGCCAT CGCAGGATTTCTGGAAAACGGGTGGGAGGGAATGGTGGACGGTTGGTACGGCTTCCGTCAC CAGAACGCCCAGGGCACGGGTCAGGCCGCAGACTATAAAAGTACCCAGGCGGCCATTGATC AGATAACAGGCAAGCTCAACCGGCTGGTAGAAAAAACCAATACAGAGTTTGAGAGCATAGA GTCCGAGTTTAGCGAGATAGAACATCAAATAGGAAATGTCATCAACTGGACCAAGGACAGC ATCACGGATATTTGGACTTACCAGGCCGAATTACTGGTTGCTATGGAGAACCAGCACACTA TTGATATGGCAGATTCTGAAATGTTAAACTTATATGAACGCGTGAGAAAGCAGTTGAGGCA GAATGCTGAGGAGGACGGGAAGGGCTGCTTTGAAATATACCATGCCTGCGACGATAGCTGT ATGGAGAGCATCAGGAACAATACATACGATCACAGTCAATACCGCGAGGAGGCTTTACTCA ACCGGCTCAACATAAACCCCGTCACTCTCTCTTCGGGCTACAAGGATATTATTCTGTGGTT TTCATTCGGCGCTTCCTGCTTCGTTCTCCTAGCCGTAGTAATGGGCCTCTTCTTCTTCTGC CTGAAAAACGGCAACATGCGGTGTACTATCTGCATT 840 ATGTACAAGATTGTGGTCATCATCGCCCTGCTGGGCGCCGTCAAGGGGCTCGATAAGATTT GCCTAGGTCACCACGCCGTCGCCAATGGCACGATTGTTAAAACACTGACCAATGAACAGGA GGAAGTGACTAACGCTACGGAAACAGTGGAATCTACAGGGATTAACAGACTTTGCATGAAG GGGCGCAAGCATAAGGACCTTGGAAATTGCCACCCAATCGGAATGCTTATCGGAACACCTG CTTGTGACCTTCATCTGACCGGCATGTGGGACACCCTGATAGAGAGGGAGAACGCCATCGC CTACTGCTATCCTGGAGCCACCGTCAATGTCGAAGCCTTAAGACAGAAAATAATGGAAAGT GGGGGTATAAACAAAATCAGCACTGGCTTCACTTATGGTTCTTCTATCAATAGCGCAGGGA CAACCAGAGCCTGCATGCGCAATGGGGGCAATAGCTTTTATGCCGAACTGAAGTGGCTGGT CTCTAAATCTAAGGGTCAAAATTTTCCTCAGACAACCAACACATACCGCAATACGGACACC GCGGAGCATCTCATTATGTGGGGGATTCACCACCCTTCAAGCACCCAGGAGAAGAATGACC TCTATGGGACACAGAGCCTGTCAATCTCAGTGGGATCTAGCACTTATCGTAACAATTTCGT TCCAGTAGTTGGTGCACGCCCCCAGGTTAATGGGCAGAGTGGGCGAATTGATTTCCACTGG ACGCTCGTGCAGCCCGGCGATAATATCACATTCAGTCACAATGGGGGGCTAATCGCCCCGT CCAGAGTTTCTAAGCTGATCGGCAGAGGATTAGGAATTCAATCCGACGCACCCATTGACAA CAATTGTGAATCAAAATGCTTCTGGCGCGGAGGGTCGATAAACACACGACTTCCTTTTCAA AACTTATCCCCAAGAACCGTGGGACAGTGCCCCAAGTACGTCAATAGAAGATCACTGATGC TGGCCACCGGTATGAGGAATGTGCCCGAACTAATCCAGGGCCGCGGGTTGTTCGGCGCTAT TGCAGGCTTTTTAGAAAACGGCTGGGAAGGGATGGTCGACGGATGGTACGGGTTCAGGCAT CAGAATGCGCAGGGCACTGGGCAGGCCGCGGATTATAAGAGTACCCAGGCGGCCATAGATC AAATAACCGGCAAGCTCAACAGGCTGGTCGAGAAGACAAACACAGAGTTTGAGTCAATAGA GTCCGAATTCTCCGAAATCGAACACCAAATAGGCAATGTGATAAACTGGACCAAGGACTCC ATCACCGATATCTGGACTTATCAGGCTGAACTGTTAGTGGCGATGGAAAACCAGCACACAA TCGATATGGCAGACTCAGAGATGCTTAATCTGTATGAACGAGTTAGAAAGCAGCTCCGGCA GAATGCCGAGGAAGACGGAAAGGGCTGCTTCGAGATCTACCACGCGTGCGATGATTCCTGT ATGGAGTCTATTCGCAATAACACGTATGATCATTCACAGTATAGAGAAGAGGCCCTCCTAA ACAGGCTCAACATCAACCCTGTGACGCTGTCGAGCGGCTATAAGGATATTATACTGTGGTT TAGTTTCGGCGCCAGTTGCTTTGTCCTTCTTGCCGTGGTAATGGGATTATTCTTCTTCTGT CTGAAAAACGGAAACATGAGATGCACAATATGTATC 841 ATGTATAAAATTGTAGTCATTATTGCCTTGTTAGGTGCAGTGAAGGGCTTAGACAAAATAT GCCTAGGTCATCACGCCGTCGCTAATGGTACAATAGTCAAGACCCTCACCAATGAACAGGA GGAGGTCACGAACGCAACAGAGACCGTGGAGTCCACAGGAATAAACCGACTGTGTATGAAG GGCAGAAAACATAAAGACTTGGGCAACTGTCACCCTATAGGCATGTTGATTGGCACACCAG CTTGTGATCTCCACCTAACCGGGATGTGGGACACCCTCATAGAACGCGAGAACGCTATCGC CTATTGTTATCCCGGGGCCACGGTTAATGTGGAAGCTCTGCGACAGAAGATCATGGAGAGC GGGGGGATTAATAAGATAAGCACTGGTTTCACCTACGGCTCAAGTATCAATTCAGCTGGCA CCACCCGAGCATGTATGAGGAATGGCGGAAATAGCTTTTATGCAGAACTGAAGTGGTTAGT CAGTAAAAGTAAAGGTCAGAACTTTCCACAGACCACCAACACATATCGCAATACTGATACA GCTGAGCACTTAATCATGTGGGGAATTCACCATCCCAGTTCCACACAAGAAAAAAATGATT TATACGGCACTCAGTCCCTTTCAATCAGCGTGGGGTCCTCTACCTACAGGAATAACTTTGT CCCCGTGGTTGGCGCCAGACCCCAGGTAAACGGTCAGTCTGGACGGATCGATTTCCACTGG ACACTGGTGCAGCCAGGTGACAATATTACCTTCAGCCACAATGGGGGCCTGATCGCCCCCT CAAGAGTGTCCAAGCTGATCGGAAGAGGGTTGGGGATCCAGTCCGATGCCCCAATCGACAA TAACTGCGAATCCAAATGTTTCTGGCGCGGAGGCTCAATAAATACCAGACTCCCTTTCCAG AACCTTTCACCAAGAACAGTCGGACAATGCCCTAAGTATGTCAATCGCCGATCGCTAATGC TTGCGACAGGGATGAGAAATGTGCCAGAGCTGATTCAAGGGCGCGGGCTGTTCGGCGCTAT CGCCGGCTTTTTAGAGAATGGTTGGGAAGGGATGGTGGATGGCTGGTATGGATTTAGGCAC CAGAACGCTCAGGGGACAGGGCAGGCTGCCGACTATAAGAGCACACAGGCAGCCATTGACC AAATCACTGGGAAATTGAACCGTCTTGTGGAAAAAACTAACACCGAGTTCGAGTCCATTGA GTCCGAGTTCTCGGAGATAGAACACCAAATCGGGAACGTCATCAATTGGACAAAAGATTCC ATCACCGATATCTGGACTTACCAGGCTGAGTTGCTGGTCGCTATGGAGAACCAGCACACGA TCGACATGGCAGACTCTGAGATGTTGAACCTGTATGAGAGAGTGCGAAAACAGCTCAGACA GAACGCTGAAGAAGACGGAAAGGGGTGCTTCGAGATCTATCATGCCTGTGACGATAGCTGT ATGGAGAGCATAAGAAACAATACGTATGATCACTCTCAGTACAGAGAAGAGGCCCTGCTAA ATCGGTTAAACATTAATCCAGTGACCCTGAGCAGCGGCTACAAGGACATCATCCTATGGTT TTCTTTCGGTGCCTCGTGCTTCGTCTTACTCGCTGTCGTCATGGGTCTGTTCTTCTTTTGC CTGAAGAACGGCAATATGCGGTGTACAATCTGTATT 842 ATGTATAAAGTGGTCGTGATTATTGCTCTGTTAGGCGCCGTGCGCGGCTTGGATAAGATCT GCCTAGGCCATCACGCCGTCGCTAACGGCACTACCGTAAAGACCCTGACCAACGAGCAGGA AGAAGTCACAAATGCTACCGAGACCGTTGAGAGCACTTCGTTGAACAAGTTATGCATGAAG GGCAGACGCTACAAGGATCTGGGTAATTGCCACCCCATAGGGATGCTCATTGGAACGCCCG TCTGTGACTTGCATTTGACCGGCACATGGGATACCCTCATCGAGCGGGAAAACGCCACAGC ATACTGCTATCCTGGGGTGACTATCAACGAGGAAGCATTGAGGCAAAAGATCATGGAATCA GGCGGGATCAGTAAGATGAGAACCGGGTTCACCTACGGGCCTTCCATCAACTCCGCCGGCA CCACCCGCAGTTGTATGAGAAACGGCGGCAATTCTTTTTATGCTGAGCTGAAGTGGTTGGT CTCTGGGACCAAGGGCCAAAATTTTCCTCAAACAACGAATACCTACCGGAATACTGACACG GCTGAACATCTGATCATCTGGGGGATTCACCACCCCTCATCCACCCAAGAGAAGAATGATC TGTATGGAACGCAGAGCCTGTCTATTTCGGTTGGAAGCAGTACATACCAGAATAACTTCGT GCCCGTTATTGGGGCCCGTCCCCAGGTCAACGGTCAGTCGGGCCGGATTGAGTTCCATTGG ACCCTGGTCCGCCCTGGTGACAACATTACTTTTTCGCATAACGGTGGGCTAATCGCACCTG ATCGAGTGTCCAAGCTGATCGGCAAAGGAATTGGTATACAGTCTGGTGCGGTAATCGATAA GGACTGTGAAAGCAAATGCTTCTGGAGAGGCGGCAGTATCATCACCGAACTCCCCTTTCAG AATCTCTCTCCACGTACAGTGGGCCAGTGTCCAAAGTATGTTAAAAAGCGGTCTCTGTTAC TAGCCACGGGGATGAGGAATGTTCCCGAGGTGGTACAAGGACGGGGCCTCTTCGGGGCGAT CGCCGGCTTCATTGAAAACGGCTGGGAGGGTATGGTTGACGGATGGTACGGATTCCGCCAC CAAAACGCCCAGGGAATCGGCCAGGCTGCCGACTACAAATCCACTCAGACCGCCATCGACC AAATTACGGGTAAACTGAACCGCCTAATCGAGAAGACAAATACTGAATTTGAGAGCATTGA GAGTGAGTTCAGCGAAATCGAGCACCAGATCGGAAATGTGATTAATTGGACAAAGGATAGT ATTACCGACATCTGGACCTACCAGGCGGAGCTCCTTGTGGCTATGGAAAACCAACACACCA TTGACATGGCCGACAGTGAAATGCTGAATCTCTACGAGCGCGTGAGAAAGCAGCTCCGGCA GAACGCCGAGGAGGACGGCAAAGGATGCTTCGAAATATATCACACATGTGACAACTCATGC ATGGAAAGTATTAGGAACAACACCTACGACCATTCCCAATACAGAGAGGAGGCCCTACTTA ACCGCCTTAACATCAATCCCGTGAAACTCTCCTCCGGTTATAAAGATATCATTTTATGGTT CAGCTTCGGGGCGAGTTGCTTTGTGCTGCTGGCTGTGATTATGGGCCTGGGATTCTTTTGC CTAAAAAACGGAAACATGCGATGCACTATCTGTATC 843 GGCAGATCCTACAACGACTTAGGGAACTGTCATCCGATAGGGATCTTAATCGGGACCCCAG CCTGCGATCTCCACCTGACTGGCACCTGGGATACCTTAATCGAGAGGGAAAACGCAGTGGC CTACTGCTATCCCGGTGCTACCGTGAATGAGGAGGCTCTGAGGCAGAAGATCATGGAGTCA GGGGGAATTTCGAAAATAAGCACCGGGTTCACTTACGGTACCAGCATCAATTCTGCTGGAA CAACTAAGGCATGTATGCGTAATGGCGGAAACTCATTTTACGCAGAGCTCAAGTGGCTAGT GAGCAAGAATAAAGGGCAGAACTTTCCGCAGACCACTAACACTTACAGAAACACAGATACC GCTGAACATTTGATTATCTGGGGCATTCACCACCCGTCGTCAACACAGGAGAAGAATGATC TGTATGGTACACAGTCACTGTCAATTTCTGTCGGATCTTCCACCTACCAGAATAATTTCGT TCCAGTGGTTGGTGCTAGGCCCCAGGTTAACGGACAATCCGGTCGCATTGACTTCCATTGG ACCCTGCTGCAGCCAGGCGATAACATTACGTTCTCGCATAACGGCGGCCTAATCGCACCTA GCAGAGTGTCAAAGTTGATTGGGAGGGGCCTTGGCATCCAGAGCGAGGCCCCCATCGACAA TGGCTGCGAGTCCAAATGCTTCTGGAAAGGGGGGTCAATCAACACCAAGCTGCCCTTTCAG AACCTCAGCCCCCGAACCGTCGGGCAGTGCCCTAAATACGTGAATAAGCGCAGTCTGATGT TAGCTACAGGGATGCGGAATGTACCCGAAATCATGCACGGGCGAGGTCTGTTCGGGGCAAT TGCAGGCTTCATTGAAAATGGGTGGGAAGGCATGGTCGATGGGTGGTATGGGTTTAGACAC CAAAACGCACAAGGAACAGGCCAGGCAGCGGACTATAAGAGCACCCAGGCAGCTATTGACC AGATTACCGGCAAGCTGAACAGGCTTATAGAGAAGACTAACACAGAATTCGAGTCCATTGA GTCAGAGTTCAGCGAGATTGAGCACCAGATCGGAAACATCATTAACTGGACTAAGGACTCA ATTACAGATATATGGACGTATCAGGCCGAACTGTTGGTGGCAATGGAGAATCAGCATACCA TTGATATGGCAGATAGTGAGATGCTGAATCTTTACGAACGCGTTCGCAAACAGTTGCGGCA GAATGCCGAAGAAGACGGCAAGGGTTGCTTTGAGATATACCACGCTTGTGACGATTCCTGC ATGGAGTCTATCAGAAACAACACGTACGATCACAGTCAGTATCGCGAGGAGGCATTACTCA ATCGACTAAATATCAACCCGGTGAAACTGTCTAGCGGATACAAAGACATCATCCTTTGGTT TTCCTTTGGCGCAAGTTGTTTGATTCTGTTGGCCGTGGTTATGGGTTTAGTCTTTTTTTGT CTCAAAAACGGTAATATGCGCTGTACGATCTGCATT 846 ATGTACAAGATCGTGGTCATCATCGCCTTGTTGGGGGCAGTGAAAGGATTGGATAAAATTT GCCTGGGACACCACGCCGTCGCCAATGGAACCATAGTCAAGACGCTGACAAACGAGCAGGA GGAAGTAACCAATGCGACTGAAACCGTGGAATCAACCGGAATCAATCGACTGTGTATGAAA GGCAGGAAGCATAAAGACCTGGGCAACTGTCACCCGATCGGGATGTTAATCGGGACACCCG CTTGTGACTTGCACCTGACCGGCATGTGGGACACTCTGATTGAGCGAGAGAATGCAATCGC CTATTGTTACCCCGGAGCCACTGTTAACGTTGAGGCCCTCAGACAGAAGATTATGGAGTCT GGCGGGATCAACAAGATCTCCACAGGGTTTACTTACGGAAGCAGCATCAACTCTGCCGGCA CTACTCGCGCTTGCATGCGTAACGGGGGTAACAGCTTCTATGCTGAACTCAAATGGCTGGT GTCTAAAAGTAAGGGCCAGAACTTTCCGCAGACGACTAATACATATAGAAATACCGATACA GCCGAGCACCTGATTATGTGGGGGATACACCACCCCAGTTCCACCCAGGAAAAGAACGACC TATATGGAACCCAGTCCCTCTCTATTAGCGTCGGCTCTTCAACTTATCGTAATAATTTTGT GCCGGTCGTCGGAGCAAGACCTCAGGTCAACGGGCAGTCCGGTCGAATAGATTTTCACTGG ACCCTAGTTCAGCCAGGAGATAATATCACATTCAGCCACAACGGAGGGTTGATAGCTCCAT CACGAGTGTCCAAGCTGATCGGCAGGGGGCTCGGCATCCAGTCCGACGCCCCAATTGATAA CAACTGTGAATCCAAGTGCTTCTGGAGAGGAGGCTCTATCAATACCCGATTGCCGTTCCAA AATCTATCCCCTAGAACAGTCGGGCAGTGCCCTAAATACGTGAATAGAAGAAGCTTAATGT TGGCAACAGGAATGAGGAACGTGCCGGAACTCATCCAGGGGCGCGGCTTATTCGGCGCTAT CGCAGGTTTTCTTGAGAATGGATGGGAGGGCATGGTTGATGGTTGGTACGGATTCAGACAC CAAAACGCTCAAGGCACCGGCCAAGCTGCCGATTATAAAAGCACTCAAGCTGCTATCGACC AGATTACCGGAAAACTTAATAGGCTGGTTGAGAAAACGAACACCGAATTCGAGAGCATCGA GAGCGAATTTAGTGAGATCGAGCATCAAATAGGCAACGTGATCAATTGGACGAAAGATTCT ATCACCGATATTTGGACTTATCAAGCCGAACTTCTAGTGGCAATGGAGAACCAGCACACAA TCGACATGGCAGATTCGGAAATGCTGAATTTATACGAGAGGGTGCGTAAACAGTTAAGGCA AAACGCCGAAGAGGACGGTAAAGGTTGCTTTGAAATTTATCACGCGTGCGATGATTCCTGT ATGGAGAGTATTCGGAATAATACATATGATCACTCCCAATATCGCGAAGAGGCATTGTTAA ACCGGCTGAATATAAATCCAGTAACCCTGTCCTCCGGGTACAAAGACATAATCCTGTGGTT CTCCTTCGGGGCTAGTTGTTTTGTTCTGCTGGCTGTGGTTATGGGATTATTCTTTTTTTGT CTGAAAAACGGGAATATGCGCTGTACAATATGCATA 847 ATGTACAAAATTGTAGTGATTATCGCTCTTCTAGGCGCCGTAAAGGGGCTTGACAAGATCT GTCTAGGACACCACGCCGTGGCCAATGGAACCATTGTAAAAACACTGACGAACGAGCAGGA GGAGGTGACAAACGCCACTGAAACAGTTGAGAGCACCGGGATTAACCGTCTCTGTATGAAG GGTAGGAAACACAAAGATCTCGGGAATTGTCATCCAATTGGAATGCTGATAGGCACTCCCG CCTGTGACCTTCACTTAACTGGCATGTGGGACACACTGATCGAGAGGGAGAATGCAATTGC GTATTGTTACCCGGGCGCCACTGTTAATGTGGAGGCGCTGAGGCAGAAAATAATGGAGTCC GGCGGAATAAATAAAATCTCTACGGGGTTCACCTACGGATCCTCCATCAACTCTGCAGGCA CAACAAGAGCCTGCATGAGAAACGGGGGCAACAGTTTTTACGCCGAGCTGAAATGGTTAGT CAGTAAATCTAAAGGGCAAAATTTCCCTCAGACGACCAACACCTACCGGAACACCGATACC GCTGAGCATCTCATCATGTGGGGTATCCATCACCCTTCCAGCACTCAGGAGAAAAACGACC TGTACGGTACTCAATCCCTCTCTATCTCAGTCGGAAGCTCCACATACCGCAATAATTTCGT GCCTGTGGTCGGGGCCCGCCCGCAGGTTAACGGACAGTCAGGACGGATTGACTTCCACTGG ACTCTGGTGCAGCCCGGTGACAACATTACGTTTAGCCATAACGGTGGTCTCATTGCCCCGT CGCGTGTATCCAAGCTGATTGGCCGGGGGTTAGGGATTCAAAGTGACGCACCCATCGACAA CAATTGCGAATCGAAGTGTTTTTGGAGAGGCGGCAGTATTAATACCCGGTTGCCATTCCAA AACCTCTCCCCAAGAACAGTTGGCCAGTGTCCAAAATATGTCAACCGGCGGTCCCTTATGC TCGCCACCGGCATGCGAAACGTACCCGAACTGATCCAAGGCCGCGGTCTGTTTGGAGCTAT CGCAGGCTTCCTGGAGAACGGGTGGGAGGGCATGGTCGACGGATGGTATGGTTTTAGGCAC CAGAATGCACAAGGGACGGGTCAAGCCGCCGATTACAAGAGCACACAGGCGGCCATCGACC AAATCACTGGGAAACTGAATAGACTGGTGGAGAAGACCAACACTGAGTTCGAAAGCATCGA ATCAGAATTTAGCGAAATAGAACACCAGATCGGCAATGTGATTAACTGGACAAAGGATAGC ATAACAGACATCTGGACATATCAGGCTGAACTGCTTGTCGCGATGGAGAACCAGCACACCA TAGATATGGCAGATAGTGAAATGCTCAATTTATACGAGCGGGTGAGAAAACAGCTTAGACA GAACGCTGAAGAGGACGGCAAGGGGTGCTTTGAGATATACCACGCCTGCGACGACAGCTGC ATGGAAAGTATCAGGAACAATACATATGACCACTCACAGTATCGCGAAGAGGCACTTCTCA ATAGACTAAACATCAATCCCGTGACACTGAGTAGTGGATATAAAGATATTATATTATGGTT CTCTTTTGGGGCGTCATGTTTCGTGCTTCTGGCCGTGGTGATGGGTCTCTTCTTCTTCTGT CTTAAAAATGGCAATATGCGGTGCACCATTTGCATA 848 ATGTACAAAATCGTACTGGTGCTGGCATTGCTCGGGGCAGTGCACGGCCTGGACAAGATAT GCCTGGGACACCACGCTGTGCCTAACGGTACCATTGTGAAGACTCTGACGAATGAGAAGGA AGAGGTGACGAACGCAACGGAGACGGTCGAGTCCAAGAGCCTCGATAAGCTGTGTATGAAG AACAGGAACTACAAGGACCTCGGGAATTGTCATCCAATTGGCATGGTGGTGGGCACTCCCG CCTGCGACCTCCATCTGACTGGTACATGGGATACCCTAATAGAGCGGGACAATAGTATCGC CTACTGTTATCCCGGCGCCACCGTGTCAGAGGAGGCCCTGCGACAGAAAATAATGGAGTCC GGCGGCATTGATAAGATTTCCACTGGGTTTACATACGGTAGCTCCATTAATTCTGCGGGAA CTACCAAGGCTTGTATGAGAAATGGCGGTAACTCTTTCTATAGCGAGTTAAAATGGCTGGT GAGCAAGAATAAGGGCCAAAATTTCCCCCAGACTACGAACACCTACAGAAACACCGACAGT GTTGAGCACCTGATTATATGGGGGATACATCATCCCAGTTCTACTCAGGAGAAAAACGATT TATACGGCACTCAAAGTCTGAGTATCTCTGTGGGGTCTAGCACATACCAGAACAACTTCGT CCCAGTGGTTGGGGCAAGGCCGCAGGTGAATGGACAATCAGGGAGAATCGATTTCCACTGG ACAATGGTACAGCCTGGGGATAATATCACCTTTTCTCATAACGGCGGACTTATAGCCCCCA ACCGCGTGAGCAAGCTAAAGGGAAGAGGCCTAGGAATTCAAAGCGGTGCTTCGGTGGACAA TGACTGCGAGAGCAAGTGCTTCTGGAAAGGTGGCTCCATCAATACTAAGTTGCCTTTTCAG AACTTGAGCCCGAGAACCGTTGGCCAGTGCCCTAAATATGTGAACAAAAAGTCACTCCTGC TCGCCACAGGGATGAGGAATGTCCCCGAAGTGGCTCAGGGTCGCGGGCTCTTCGGAGCCAT CGCCGGATTCATCGAGAACGGCTGGGAAGGGATGGTAGACGGCTGGTATGGCTTTAGGCAT CAAAACGCCCAGGGGACAGGGCAAGCCGCTGACTATAAGAGTACCCAGGCAGCCATCGACC AGATCACTGGGAAATTAAATCGGCTGATTGAAAAGACGAACACCGAATTTGAAAGCATCGA GTCAGAGTTCTCCGAGATAGAGCATCAAATTGGGAACGTGATTAACTGGACGAAGGATAGC ATCACCGATATTTGGACATACCAGGCGGAGCTGCTGGTGGCCATGGAGAATCAACATACAA TCGACATGGCCGACTCTGAGATGTTGAATCTCTACGAAAGGGTGAGAAAGCAGTTAAGGCA GAATGCCGAGGAGGATGGGAAAGGATGCTTCGAGATCTATCACAAATGCGATGACAATTGT ATGGAATCTATTCGTAACAATACTTACGACCACACTCAGTATCGTGAGGAAGCGCTGTTGA ATCGGCTCAATATCAATCCAGTGAAGCTGTCATCTGGCTACAAAGATGTGATATTATGGTT TTCTTTTGGGGCATCTTGCTTCGTGCTGCTGGCTGTCATTATGGGACTTGTATTTTTTTGT TTGAAGAATGGAAACATGCGCTGCACAATCTGCATC 849 ATGTATAAGATAGTGGTCATAATTGCCCTGCTGGGGGCGGTGAAGGGCCTGGACAAGATTT GTCTGGGTCATCATGCTGTGGCAAACGGTACGATCGTTAAGACCCTGACGAATGAACAAGA GGAGGTGACTAACGCTACCGAAACCGTGGAGTCCACCGGCATAAACCGCCTTTGCATGAAG GGGAGGAAGCACAAGGACCTCGGTAACTGTCACCCAATCGGCATGTTAATTGGCACACCAG CTTGTGATCTGCACCTGACCGGAATGTGGGATACACTCATTGAAAGAGAAAACGCTATCGC GTATTGCTACCCTGGAGCAACTGTTAATGTCGAGGCTTTGCGCCAAAAAATAATGGAAAGT GGCGGTATCAATAAAATCTCAACAGGGTTTACCTACGGGAGCAGTATCAACTCAGCCGGAA CAACCCGGGCCTGCATGCGCAATGGCGGCAACTCTTTTTACGCTGAACTGAAATGGTTGGT GTCAAAATCAAAGGGTCAAAACTTTCCTCAAACTACAAATACATATCGGAACACCGATACA GCTGAGCACTTAATAATGTGGGGGATCCACCACCCTTCTTCAACTCAGGAAAAGAATGATC TGTATGGCACTCAGTCACTCTCCATTAGCGTAGGGTCATCTACCTATAGAAATAATTTCGT ACCAGTGGTAGGTGCAAGGCCCCAGGTGAACGGCCAGAGTGGCAGAATAGACTTCCACTGG ACTCTTGTTCAGCCAGGGGATAACATTACATTCTCGCACAACGGCGGCCTGATAGCCCCAT CTAGGGTGTCTAAGCTAATTGGCAGAGGTCTGGGCATCCAATCCGACGCACCAATTGACAA CAATTGCGAAAGTAAGTGTTTCTGGAGAGGAGGGTCAATTAATACAAGATTGCCGTTTCAA AATCTGTCCCCGAGAACAGTGGGACAGTGCCCAAAATATGTAAATAGACGGTCACTGATGT TAGCTACCGGCATGCGAAACGTCCCCGAGCTGATTCAGGGTAGAGGCCTGTTCGGAGCTAT TGCAGGGTTTTTGGAAAATGGGTGGGAGGGCATGGTGGACGGATGGTACGGGTTCCGACAC CAGAATGCCCAGGGAACCGGCCAGGCGGCTGACTACAAGTCTACACAGGCAGCAATTGACC AAATCACCGGAAAGTTGAACCGCCTTGTAGAGAAAACAAACACGGAATTTGAATCAATTGA ATCAGAGTTTTCCGAGATAGAGCACCAGATCGGGAATGTCATAAATTGGACAAAGGATTCT ATTACGGATATTTGGACCTACCAAGCAGAACTGCTTGTGGCTATGGAAAATCAGCACACCA TAGATATGGCCGACAGTGAGATGCTGAACCTGTACGAGCGGGTAAGAAAGCAGTTGCGCCA GAACGCAGAGGAAGACGGGAAAGGCTGCTTCGAAATCTATCACGCCTGTGACGACTCATGC ATGGAAAGTATCAGGAATAATACATACGATCATTCCCAATACCGTGAGGAAGCACTACTCA ACCGGCTGAATATCAACCCCGTTACACTCTCCTCAGGTTATAAAGACATAATCCTGTGGTT CTCCTTCGGCGCTAGCTGCTTTGTCCTGTTGGCCGTAGTAATGGGGCTGTTCTTCTTTTGC CTTAAAAACGGGAACATGCGATGTACTATCTGCATT 850 ATGTACAAGGTCGTAGTGATTATCGCCCTCCTTGGCGCCGTTAAAGGCCTAGACAAGATCT GTCTGGGACATCACGCCGTCGCTAATGGCACAATAGTGAAAACGCTCACTAATGAGCAGGA GGAAGTAACCAACGCCACAGAAACGGTCGAATCCACCGGCATAAATCGGCTTTGCATGAAG GGGCGTAAACATAAGGACCTGGGGAACTGTCACCCAATAGGGATGCTGATCGGAACACCTG CTTGTGACCTCCACCTGACAGGCACCTGGGATACGTTGATCGAGCGGGAGAACGCTATCGC ATACTGCTACCCCGGCGCTACCGTCAATGTGGAAGCACTGCGTCAGAAGATAATGGAATCA GGAGGCATTGATAAGATCTCAACAGGGTTTACCTACGGCTCTAGTATCAATAGCGCAGGTA CCACCAGGGCATGCATGCGCAATGGTGGCAACAGTTTCTACGCAGAGCTGAAGTGGCTGGT GTCTAAAAATAAAGGCCAGAACTTCCCTCAGACCACAAACACTTACCGCAATACAGATACT GCAGAGCATCTGATTATGTGGGGGATCCACCACCCTTCCTCCATTCAAGAGAAGAACGACC TGTACGGCACTCAGAGCTTATCAATATCGGTGGGTTCCTCCACTTACCGTAACAATTTCGT CCCCGTAGTCGGGGCTAGGCCTCAGGTGAATGGTCAGTCAGGGAGGATAGACTTTCACTGG ACGCTGGTTCAGCCAGGCGACAATATAACCTTCTCACACAACGGGGGTCTGATTGCTCCTT CTAGGGTGTCAAAGCTGATCGGGAGAGGACTGGGTATACAAAGCGATGCCCCCATCGATAA TAACTGTGAAAGTAAGTGTTTTTGGCGCGGAGGGAGCATTAACACGCGGCTGCCTTTTCAG AACCTGTCCCCCCGGACTGTGGGCCAGTGTCCCAAGTACGTGAACCGCAGGTCACTCATGC TAGCCACGGGTATGAGAAATGTGCCAGAGTTAATTCAGGGCCGCGGTCTGTTTGGGGCTAT TGCAGGTTTTCTGGAGAACGGGTGGGAGGGCATGGTGGACGGTTGGTACGGCTTTAGGCAT CAGAACGCACAGGGTACTGGACAGGCAGCCGATTACAAGAGCACTCAGGCAGCGATAGACC AGATAACTGGCAAGCTCAACCGTTTAGTGGAGAAGACCAACACCGAATTTGAAAGTATTGA GTCCGAGTTCTCAGAGATTGAGCATCAGATCGGCAATGTCATTAATTGGACAATGGATTCG ATCACCGATATATGGACCTATCAGGCCGAGTTGCTGGTCGCCATGGAAAATCAACACACTA TAGATATGGCAGATTCCGAAATGCTGAATCTCTATGAGAGGGTGAGAAAACAACTGAGGCA AAATGCGGAGGAAGACGGGAAAGGTTGCTTCGAAATTTACCATGCTTGCGATGATAGTTGC ATGGAGTCCATCCGGAATAACACGTATGATCACAGCCAATACCGGGAAGAAGCCCTGCTTA ACCGGCTTAACATAAATCCTGTGACTCTCTCATCAGGATATAAGGATATCATCCTCTGGTT CTCTTTCGGGGCCAGCTGCTTTGTTTTGTTAGCCGTGGTGATGGGACTCGTGTTCTTCTGC TTAAAAAACGGCAATATGCGTTGCACCATCTGCATC 851 ATGTATAAGATCGTCGTTATTATTGCCCTGCTTGGTGCTGTCAAGGGGTTGGACAAAATTT GCTTGGGCCACCACGCAGTGGCTAACGGCACTATAGTCAAAACCCTGACGAACGAGCAGGA GGAGGTGACAAACGCCACTGAGACCGTGGAATCTACGGGAATCAACAGGCTCTGCATGAAG GGGCGCAAACACAAAGACCTCGGGAACTGCCACCCTATCGGGATGCTCATAGGTACTCCAG CGTGTGACCTGCACTTAACAGGCACTTGGGATACCCTTATTGAACGGGAAAATGCTATCGC TTACTGCTACCCGGGCGCGACCGCCAACGTGGAAGCATTACGCCAAAAGATAATGGAATCA GGCGGCATAGATAAAATCTCCACCGGATTTACATACGGGTCTAGCATAAATTCTGCCGGCA CCACTAGAGCCTGTATGAGAAACGGCGGAAATTCATTCTACGCTGAGCTGAAATGGCTGGT CTCAAAGTCTAAGGGGCAGAATTTCCCCCAGACCACGAATACGTACCGGAACACAGATACC GCCGAGCATCTGATCATGTGGGGAATCCATCACCCCAGTTCAATCCAGGAGAAGAATGACT TATACGGTACACAATCCCTGTCCATATCAGTAGGTAGCTCTACATATCGGAACAATTTCGT GCCTGTCGTCGGGGCTAGGCCTCAGGTAAACGGCCAGTCCGGTAGAATCGATTTTCACTGG ACCCTCGTCCAGCCTGGGGACAATATAACGTTTAGTCACAACGGAGGTCTCATCGCCCCCA GCCGGGTATCTAAGCTTATTGGCAGGGGCCTGGGTATTCAGAGCGACGCCCCAATTGACAA TAATTGCGAAAGCAAGTGCTTCTGGAGGGGTGGAAGTATTAACACAAGACTGCCTTTCCAA AACCTGAGCCCTAGAACTGTGGGACAGTGCCCAAAATACGTCAACAGGAGATCACTTATGC TGGCGACAGGAATGCGCAATGTACCTGAACTTATTCAAGGGCGAGGACTGTTTGGTGCCAT AGCTGGGTTCCTGGAAAACGGTTGGGAGGGAATGGTGGACGGCTGGTACGGGTTTAGACAC CAAAACGCACAAGGAACCGGCCAGGCTGCCGATTATAAGTCCACACAAGCAGCCATCGATC AAATTACCGGTAAGCTGAATCGGTTAGTTGAAAAAACCAATACCGAGTTTGAATCCATCGA GAGTGAGTTCTCAGAGATCGAGCACCAGATAGGCAATGTGATCAACTGGACAATGGATTCA ATTACCGATATCTGGACCTACCAGGCTGAGCTGCTGGTGGCCATGGAAAATCAGCATACAA TTGATATGGCCGACAGTGAGATGCTGAACTTGTATGAAAGAGTTAGAAAACAGCTGAGGCA AAATGCCGAAGAGGATGGCAAGGGATGTTTTGAAATCTATCATGCGTGTGATGATAGCTGT ATGGAATCCATCAGGAACAATACATACGATCACTCACAGTATAGAGAAGAAGCACTCCTGA ACAGATTAAATATCAATCCAGTGACCTTATCATCTGGCTACAAGGATATAATTCTTTGGTT TTCGTTTGGGGCTTCCTGCTTCGTGTTGCTGGCCGTGGTCATGGGTCTAGTGTTTTTTTGC TTGAAAAACGGAAATATGCGGTGTACCATCTGTATC 852 ATGTACAAGATTGTGGTTATAATTGCGCTTCTGGGAGCTGTGAAGGGATTGGACAAGATCT GCCTTGGGCACCATGCCGTTGCAAATGGTACCATTGTGAAGACGCTGACCAATGAGCAGGA AGAGGTGACCAATGCTACAGAGACAGTGGAGTCCACTGGCATCAACCGACTCTGTATGAAA GGTAGAAAACACAAAGATCTCGGCAATTGCCATCCTATAGGTATGCTGATTGGTACGCCTG CCTGTGACCTCCATCTGACTGGCATGTGGGACACGCTGATCGAAAGGGAGAATGCCATTGC GTACTGTTATCCTGGCGCTACGGTGAACGTGGAAGCCTTACGGCAGAAGATCATGGAATCC GGCGGGATCAATAAGATTAGCACCGGATTCACTTACGGATCTTCTATCAACAGCGCTGGCA CCACTAGGGCATGCATGAGAAACGGCGGGAATAGTTTTTACGCTGAGCTTAAGTGGTTGGT TTCTAAGAGTAAGGGACAGAACTTCCCTCAGACCACTAATACCTACAGGAACACCGACACC GCAGAGCATTTAATCATGTGGGGAATCCACCATCCATCCTCCACTCAGGAAAAGAATGACT TATACGGAACACAGAGCCTTTCCATATCTGTCGGTTCCTCCACATATAGAAATAATTTTGT GCCCGTGGTCGGTGCACGACCTCAGGTGAATGGCCAGTCAGGAAGAATCGATTTTCACTGG ACCCTGGTACAGCCTGGCGACAATATCACCTTCAGCCATAACGGCGGTCTGATCGCCCCTA GTCGGGTGAGTAAATTGATAGGTCGGGGACTGGGAATCCAGAGTGATGCTCCTATTGATAA TAATTGCGAGTCAAAATGTTTTTGGCGCGGCGGCTCTATTAACACCAGATTACCTTTCCAG AACCTGAGCCCTCGGACTGTTGGACAGTGTCCTAAATATGTGAATCGCAGGTCTCTGATGC TGGCTACAGGCATGAGGAACGTGCCTGAGCTCATCCAGGGAAGGGGGCTGTTCGGGGCCAT CGCTGGATTCCTGGAAAACGGATGGGAGGGAATGGTCGATGGTTGGTACGGTTTTCGGCAT CAGAATGCTCAAGGGACGGGCCAGGCGGCTGATTATAAGTCAACGCAGGCGGCCATAGACC AGATCACCGGAAAGCTCAACCGCCTGGTGGAGAAGACAAATACAGAGTTTGAGTCTATAGA GTCCGAGTTTTCCGAAATCGAACACCAGATCGGGAATGTGATAAACTGGACCAAAGATTCT ATCACTGACATTTGGACTTACCAGGCAGAACTATTGGTGGCCATGGAAAATCAGCACACCA TCGACATGGCCGACTCTGAAATGCTGAACTTGTATGAGAGAGTGCGCAAGCAGCTGCGACA AAATGCCGAAGAAGACGGAAAGGGCTGTTTTGAAATCTATCATGCTTGTGATGACTCTTGC ATGGAATCTATTAGGAACAATACCTATGATCATTCTCAGTACCGGGAAGAAGCATTGCTGA ACCGCTTGAATATAAACCCAGTGACGCTGTCATCTGGTTATAAAGACATTATCCTGTGGTT TAGCTTTGGTGCCTCATGCTTTGTACTCCTAGCCGTAGTCATGGGCCTGTTTTTCTTCTGC CTGAAGAACGGGAACATGCGATGCACTATTTGCATC 853 ATGTACAAGATCGTGGTGATCATAGCCTTACTGGGGGCCGTAAAAGGTCTGGATAAGATTT GTCTGGGCCACCACGCTGTCGCCAATGGTACCATTGTGAAGACACTAACCAACGAGCAGGA GGAGGTCACAAACGCTACCGAGACGGTTGAATCTACTGGTATAAACCGCCTTTGCATGAAG GGACGCAAACATAAGGATCTGGGGAACTGTCACCCCATTGGTATGCTGATCGGAACCCCTG CATGTGACCTACACCTGACCGGAATGTGGGATACCTTAATAGAGCGAGAGAACGCGATCGC CTACTGTTATCCGGGGGCTACGGTGAACGTTGAGGCTCTGAGGCAGAAGATAATGGAAAGT GGGGGCATCAACAAGATTAGTACCGGATTCACTTATGGTAGTAGCATTAATAGTGCTGGGA CTACCAGAGCATGTATGAGAAATGGCGGGAACAGCTTCTATGCCGAGCTGAAGTGGCTAGT GAGCAAGAGCAAGGGCCAAAACTTTCCCCAAACGACCAACACATACCGCAATACCGATACA GCAGAGCATCTCATAATGTGGGGAATCCACCACCCTAGTTCAACCCAGGAGAAGAACGATC TTTATGGAACTCAGTCCCTGTCTATCAGCGTGGGGAGTTCTACATATCGCAATAACTTTGT GCCAGTCGTGGGGGCCCGACCACAGGTAAACGGTCAGTCTGGTCGAATTGACTTTCATTGG ACCTTGGTCCAGCCGGGCGATAATATCACATTTTCCCATAATGGAGGCCTGATAGCCCCTT CCAGAGTTAGCAAATTGATAGGCCGAGGACTCGGGATCCAGAGCGATGCACCCATCGACAA CAACTGCGAGAGCAAATGCTTCTGGCGGGGCGGAAGCATTAACACTAGATTACCCTTCCAG AACCTTAGTCCTCGCACCGTGGGCCAGTGCCCTAAATATGTGAACCGGCGCTCACTGATGC TGGCCACAGGCATGAGGAATGTCCCCGAGCTGATCCAGGGCAGAGGACTCTTCGGTGCTAT CGCAGGATTTCTTGAGAACGGATGGGAAGGAATGGTAGACGGATGGTACGGGTTCCGACAT CAGAACGCTCAGGGCACTGGCCAAGCAGCCGACTACAAATCCACACAGGCGGCCATCGATC AGATAACAGGCAAACTGAATCGGCTAGTAGAGAAGACCAACACCGAATTCGAATCAATCGA GTCTGAATTCAGCGAGATAGAGCACCAAATCGGGAATGTGATTAACTGGACAAAGGATTCC ATAACCGACATTTGGACCTACCAAGCCGAACTGCTGGTCGCGATGGAAAACCAACATACCA TCGACATGGCAGACTCCGAAATGCTGAATCTGTACGAACGTGTGCGGAAACAGCTGAGACA GAATGCTGAAGAAGACGGGAAAGGCTGTTTTGAAATCTACCACGCCTGCGACGACTCATGC ATGGAAAGCATCAGGAATAACACTTATGACCATTCCCAGTACCGGGAAGAAGCACTCCTGA ACCGGTTGAACATTAATCCGGTTACCTTGAGCTCTGGATATAAAGACATCATCCTATGGTT CAGCTTCGGCGCATCCTGCTTTGTTCTGCTTGCAGTGGTCATGGGGCTGTTCTTTTTTTGC CTGAAGAATGGCAACATGAGATGTACCATTTGCATC 854 ATGTATAAGATAGTAGTCATCATAGCTCTCTTGGGCGCCGTGAAAGGGCTGGACAAGATCT GTCTGGGTCATCATGCCGTGGCCAACGGAACAATCGTGAAAACCTTGACTAATGAGCAGGA GGAGGTGACCAATGCGACCGAGACCGTTGAAAGTACGGGCATTAATAGGCTCTGTATGAAG GGTAGGAAACATAAGGACCTTGGGAACTGTCACCCCATTGGAATGCTGATTGGGACTCCTG CATGTGACTTACACTTAACAGGCATGTGGGACACTCTGATTGAGAGGGAGAACGCCATTGC CTATTGTTATCCCGGCGCCACCGTGAACGTGGAGGCACTGCGGCAGAAGATAATGGAAAGC GGAGGGATTAATAAAATCAGCACCGGATTCACTTATGGTAGTTCTATTAATTCCGCCGGGA CAACAAGGGCATGTATGAGGAACGGAGGTAATTCCTTCTACGCGGAGCTGAAGTGGCTGGT CTCTAAGTCCAAGGGGCAGAACTTTCCCCAGACTACAAACACCTACCGAAATACAGATACC GCTGAGCACCTGATCATGTGGGGAATTCATCACCCTTCATCAACACAAGAGAAGAACGACC TGTACGGCACACAGTCACTGTCAATCTCAGTAGGGAGCTCGACATATAGAAATAATTTCGT CCCGGTGGTGGGCGCTCGGCCGCAGGTTAATGGCCAGAGTGGTAGAATCGACTTTCACTGG ACGCTGGTCCAGCCAGGCGATAATATCACGTTCTCACACAATGGAGGCCTGATAGCCCCAA GCCGCGTGTCCAAGCTGATAGGGCGAGGACTTGGTATCCAGAGTGATGCCCCCATCGATAA CAACTGCGAATCCAAGTGTTTCTGGCGTGGCGGCTCAATTAACACCCGGCTTCCATTCCAG AACCTTAGCCCCCGCACTGTCGGACAATGCCCAAAGTATGTCAACAGGCGGAGCCTGATGC TGGCCACCGGCATGAGAAATGTGCCTGAGCTCATTCAGGGGCGGGGCCTTTTTGGGGCAAT CGCTGGCTTTCTCGAGAATGGTTGGGAGGGAATGGTTGACGGCTGGTATGGCTTTAGACAT CAGAATGCCCAGGGAACGGGCCAGGCTGCTGACTACAAGTCCACCCAGGCCGCCATCGACC AAATTACCGGGAAGCTGAATAGACTCGTCGAAAAGACCAACACTGAATTTGAGAGTATCGA GTCTGAGTTTTCCGAGATCGAACATCAAATCGGAAACGTTATCAACTGGACTAAGGACTCA ATCACCGACATTTGGACATATCAAGCGGAGCTCCTGGTGGCCATGGAAAATCAGCACACGA TCGACATGGCCGACAGTGAGATGCTGAATCTGTATGAGCGAGTCCGTAAGCAGCTTAGGCA GAACGCTGAGGAGGATGGAAAAGGATGTTTCGAGATATATCACGCCTGTGATGACTCCTGT ATGGAATCCATCAGGAACAACACATACGATCATAGTCAGTACAGGGAAGAAGCCTTGCTAA ATAGGTTGAACATCAACCCTGTCACTCTGAGTTCTGGATACAAGGACATCATATTATGGTT TTCCTTTGGCGCCTCCTGCTTCGTCCTGCTAGCAGTGGTGATGGGCCTGTTTTTTTTTTGC CTTAAAAATGGCAATATGCGGTGCACCATTTGCATA 855 ATGTATAAGATCGTTGTCATCATTGCTCTCCTCGGAGCCGTGAAAGGGCTCGATAAGATCT GTTTAGGACACCATGCCGTGGCAAACGGTACTATAGTCAAGACCCTAACAAATGAGAAAGA GGAGGTGACGAATGCCACAGAAACAGTAGAATCTACAGGACTGAACCGGCTGTGCATGAAG GGCCGCAAACACAAGGATTTAGGTAATTGTCACCCAATAGGCATGTTGATTGGAAGTCCGG CATGTGACCTGCACTTGACGGGCACATGGGATACCCTGATAGAAAGGGAGAACGCTATCGC CTACTGCTATCCGGGAGCCACGGTCAACGGGGAAGCGCTGCGGCAGAAGATTATGGAGTCG GGCGGTATAGATAAGATATCCACAGGCTTTACCTATGAATCCTCTATTAACTCAGCTGGTA CAACTCGCGCTTGCATGAGGAACGGGGGGAACAGTTTCTACGCCGAACTCAAGTGGCTTGT TTCTAAGTCTAAGGGCCAGAATTTCCCACAGACTACCAATACCTATAGAAACACCGACACG GCTGAGCACCTTATTATGTGGGGTATTCACCACCCCTCAAGCACTCAGGAGAAGAACGACC TCTATGGTACCCAGTCCCTTTCCATCTCCGTTGGTAGTTCTACCTACCGCAACAATTTTGT TCCCGTGGTCGGTGCAAGACCACAGGTTAACGGCCAGAGTGGGCGCATCGATTTCCACTGG ACGTTGGTCCAGCCTGGGGATAACATCACCTTTTCCCACAACGGGGGATTAATCGCACCCT CTCGGGTCTCTAAGCTGATCGGACGAGGACTGGGAATCCAAAGTGACGCACCAATAGATAA TAATTGCGAGAGCAAATGCTTCTGGCGCGGTGGGTCAATCAATACACGGCTGCCGTTTCAG AATCTATCACCAAGGACTGTGGGACAGTGCCCCAAATATGTAAATAAGCGGTCCCTGATGC TCGCCACTGGTATGCGGAACGTGCCTGAGCTAATGCAAGGAAGGGGCCTGTTTGGGGCCAT TGCCGGCTTTCTCGAAAACGGGTGGGAGGGCATGGTGGACGGATGGTACGGTTTCCGGCAC CAGAATGCTCAAGGCACCGGTCAGGCTGCCGATTATAAAAGCACCCAAGCCGCTATCGATC AGATCACTGGCAAGTTAAACAGGCTGGTAGAAAAAACTAATACTGAATTCGAGTCCATTGA GTCCGAGTTCTCTGAGATTGAGCATCAGATCGGGAATGTTATTAACTGGACGAAAGACAGT ATTACGGATATCTGGACATATCAAGCCGAGCTCCTGGTCGCTATGGAAAACCAACACACTA TCGACATGGCCGACAGCGAAATGTTGAATCTTTATGAAAGAGTGAGGAAGCAGCTGCGTCA GAACGCAGAGGAGGATGGGAAAGGATGTTTTGAGATCTACCACGCCTGTGACGATTCCTGC ATGGAGAGTATTAGAAACAACACATACGACCACAGCCAGTACCGGGAAGAGGCCCTATTGA ACAGGCTTAATATTAATCCAGTAACCCTGTCGAGTGGGTATAAAGATATTATACTGTGGTT CTCCTTTGGCGCTTCTTGCTTTGTGCTGCTCGCGGTAGTTATGGGTTTGGTGTTTTTTTGC CTCAAGAACGGAAATATGCGTTGCACCATCTGTATC 856 ATGTATAAGATCGTGGTCATCATCGCCCTGCTTGGAGCTGTAAAAGGTCTCGACAAGATTT GTCTTGGACATCATGCTGTGGCAAATGGCACCATTGTAAAGACCCTGACTAATGAGCAAGA AGAAGTAACCAACGCAACTGAGACCGTAGAGTCAACCGGCATTAATCGGCTCTGCATGAAG GGAAGGAAGCACAAAGATCTCGGCAATTGTCACCCAATAGGCATGTTGATTGGAACCCCTG CTTGTGACCTGCATCTCACGGGGATGTGGGATACTTTGATTGAAAGGGAAAACGCAATTGC GTATTGTTACCCGGGAGCCACCGTGAACGTCGAGGCCCTCCGACAAAAGATCATGGAATCA GGAGGGATCAACAAAATAAGCACTGGGTTTACCTATGGAAGTTCGATCAACTCAGCCGGGA CAACGCGCGCTTGCATGAGGAATGGCGGAAATTCCTTCTACGCTGAACTCAAATGGCTCGT GTCGAAATCAAAGGGTCAGAACTTCCCACAGACTACTAATACCTACAGAAATACTGACACA GCGGAGCATTTGATCATGTGGGGCATACACCACCCTTCTTCCACACAGGAGAAGAATGACC TTTACGGCACGCAGAGTCTGTCCATCAGCGTAGGAAGCTCAACCTACAGAAATAATTTCGT TCCCGTGGTGGGGGCTCGACCACAGGTTAACGGGCAGTCCGGTCGTATTGATTTTCATTGG ACATTGGTGCAGCCCGGCGATAACATTACTTTTAGCCACAACGGAGGCCTAATTGCCCCTA GCAGAGTCTCCAAACTGATCGGGAGGGGACTGGGGATACAGTCAGATGCCCCTATCGACAA CAATTGTGAGAGCAAGTGTTTCTGGCGAGGCGGAAGCATTAACACCCGGTTACCCTTTCAG AACCTATCTCCAAGAACTGTGGGTCAGTGCCCAAAATACGTGAACAGACGGTCTCTGATGT TGGCTACTGGTATGCGCAACGTTCCGGAACTAATTCAAGGCAGAGGACTGTTCGGCGCCAT CGCAGGGTTCCTCGAGAACGGGTGGGAGGGGATGGTCGATGGGTGGTACGGCTTTAGGCAT CAGAACGCTCAGGGGACTGGTCAGGCCGCCGATTACAAAAGCACGCAAGCTGCTATAGATC AGATCACAGGGAAACTGAATCGCCTCGTTGAGAAAACTAACACCGAATTTGAATCAATAGA ATCCGAATTCAGTGAAATCGAGCACCAGATAGGGAACGTAATCAACTGGACCAAAGACAGT ATTACAGACATCTGGACATACCAGGCGGAACTTTTAGTCGCTATGGAGAATCAGCACACAA TAGACATGGCCGACAGCGAAATGTTGAACCTGTACGAACGAGTAAGGAAGCAGCTGAGGCA AAACGCAGAAGAGGACGGAAAGGGCTGCTTTGAGATATACCACGCATGTGATGATAGCTGT ATGGAGTCAATTCGGAACAATACATATGATCACTCTCAATACCGTGAGGAAGCTCTGCTCA ATCGTCTGAATATTAACCCAGTGACTCTTTCCAGTGGGTACAAAGACATCATTCTTTGGTT TTCCTTCGGAGCTTCCTGCTTTGTGCTGCTGGCAGTCGTTATGGGATTGTTCTTTTTCTGC CTGAAGAACGGGAACATGCGCTGTACTATATGTATC 857 ATGTACAAGGTAGTGGTAATAATTGCTCTGCTGGGAGCCGTGAGAGGTCTGGATAAAATCT GTTTGGGTCACCACGCCGTCGCCAACGGGACGATCGTCAAAACACTAACAAATGAGCAAGA AGAAGTGACCAACGCAACAGAGACAGTGGAGAGTAAGAGCCTGGGAAAGCTTTGCATGAAG GGCCGCTCATATAACGACCTGGGCAACTGTCACCCCATCGGTATTCTGATTGGGACTCCAG CTTGCGACTTGCATCTGACCGGCACCTGGGACACACTCATCGAGAGAGAAAACGCAGTGGC TTACTGCTACCCTGGCGCTACCGTCAATGAAGAAGCCCTGCGACAGAAGATTATGGAGAGC GGTGGGATCAGCAAAATCTCCACCGGTTTCACCTATGGAACCTCCATTAACAGCGCAGGCA CAACAAAAGCTTGCATGAGGAATGGCGGCAACTCGTTCTATGCTGAACTGAAATGGCTGGT GTCCAAAAATAAGGGTCAGAATTTCCCTCAGACTACCAACACTTACAGGAACACGGATACA GCAGAGCACCTGATTATATGGGGGATTCACCACCCTTCGTCTACCCAAGAGAAAAATGACC TGTACGGAACTCAGAGCCTTTCAATATCCGTGGGGTCCAGTACATATCAAAATAATTTTGT CCCCGTGGTTGGCGCCCGTCCACAGGTTAACGGTCAGTCAGGGCGGATCGATTTTCATTGG ACCTTACTTCAGCCCGGAGACAATATCACTTTTTCTCACAACGGAGGACTCATCGCCCCCT CCCGTGTGTCCAAGCTCATAGGACGGGGCCTGGGTATCCAGAGCGAGGCCCCCATCGATAA CGGCTGCGAGAGCAAATGTTTTTGGAAGGGAGGGAGTATAAACACTAAGCTCCCATTCCAA AATTTAAGTCCACGTACTGTGGGCCAGTGTCCCAAGTATGTGAACAAAAGAAGCTTGATGC TGGCAACTGGGATGCGGAACGTGCCTGAGATCATGCACGGTCGGGGCCTGTTTGGCGCTAT CGCAGGGTTTATTGAAAATGGCTGGGAGGGCATGGTTGATGGGTGGTACGGGTTTAGGCAT CAGAATGCCCAGGGCACTGGTCAGGCGGCCGATTACAAGAGTACTCAGGCTGCCATCGACC AGATCACCGGCAAGCTGAACCGGTTGATCGAAAAGACAAACACTGAATTCGAGAGTATCGA AAGCGAATTTTCTGAGATCGAGCACCAAATCGGGAATATAATTAATTGGACAAAGGACTCG ATCACTGACATATGGACATACCAAGCCGAGCTGCTGGTGGCCATGGAAAACCAGCATACCA TAGACATGGCCGATTCAGAAATGCTTAATCTTTACGAGCGTGTTAGGAAGCAACTGAGGCA GAATGCCGAAGAGGACGGTAAGGGGTGCTTTGAGATTTATCACGCATGTGACGACAGCTGT ATGGAGTCCATTAGAAATAATACCTACGATCACAGTCAGTATAGAGAAGAGGCATTGCTTA ATAGGCTGAACATAAATCCCGTCAAGCTGTCTTCGGGGTACAAGGACATTATCCTGTGGTT CAGCTTTGGCGCATCGTGTCTGATATTACTGGCCGTCGTGATGGGATTAGTGTTTTTCTGC TTAAAGAACGGTAACATGCGCTGTACTATCTGTATC 858 ATGTACAAGATCGTGGTCATTATCGCTCTGTTAGGGGCAGTAAAAGGCCTGGACAAAATCT GCCTTGGCCATCATGCTGTGGCTAATGGTACAATTGTCAAAACCCTCACAAATGAACAGGA GGAGGTGACAAACGCCACAGAAACTGTGGAGAGTACAGGGATCAACCGTCTCTGCATGAAG GGAAGAAAGCATAAAGACCTTGGAAACTGTCATCCCATAGGCATGCTGATCGGCACTCCCG CCTGTGACCTGCACCTGACCGGTATGTGGGACACCCTGATCGAAAGGGAGAATGCCATTGC CTACTGTTATCCTGGCGCAACAGTGAACGTAGAAGCCTTAAGACAGAAGATCATGGAATCC GGAGGCATAAACAAAATTAGTACTGGATTCACCTACGGGAGCTCCATTAACTCTGCAGGCA CCACTCGGGCATGCATGCGCAACGGCGGTAACAGCTTCTATGCCGAGCTGAAGTGGTTAGT GTCCAAGTCGAAAGGCCAGAACTTTCCCCAGACGACAAACACATATCGGAACACCGATACT GCAGAACACCTGATCATGTGGGGGATTCACCACCCCAGTTCCACCCAGGAGAAGAACGATC TGTACGGTACTCAGAGCCTGTCCATAAGTGTTGGATCCTCTACATATCGGAATAATTTCGT GCCCGTGGTGGGCGCAAGACCACAGGTGAACGGCCAGTCTGGGAGAATTGACTTTCATTGG ACTCTGGTGCAACCAGGGGACAATATTACCTTCTCACATAATGGCGGCCTGATCGCACCTA GCAGGGTGTCCAAGCTGATAGGACGCGGACTCGGAATTCAGTCGGATGCACCTATCGATAA TAACTGCGAGTCTAAGTGTTTTTGGAGAGGCGGTTCAATCAATACTAGGCTTCCTTTTCAG AACCTGAGCCCCAGAACAGTGGGGCAATGCCCTAAATATGTGAATAGGCGGTCTCTGATGC TGGCCACTGGGATGAGAAATGTGCCAGAGCTGATTCAGGGTAGAGGCCTGTTCGGCGCAAT CGCAGGGTTCCTCGAAAACGGCTGGGAAGGTATGGTGGACGGATGGTACGGGTTCCGACAC CAAAACGCCCAGGGGACGGGCCAGGCCGCCGATTACAAATCAACTCAAGCCGCGATAGATC AGATAACCGGAAAGCTGAACAGACTCGTCGAGAAGACCAATACCGAGTTTGAGTCCATCGA AAGCGAGTTCTCAGAGATTGAGCATCAGATAGGGAACGTAATTAACTGGACGAAAGATAGC ATCACGGACATCTGGACATATCAGGCGGAACTACTGGTGGCAATGGAAAATCAGCATACCA TCGACATGGCCGACAGTGAGATGTTAAATCTCTATGAGCGGGTGCGGAAACAGCTGAGGCA AAACGCTGAAGAAGACGGAAAAGGGTGCTTTGAGATCTACCATGCCTGCGACGATAGCTGC ATGGAGTCAATTCGGAACAATACTTATGACCACTCCCAGTATCGGGAGGAGGCCCTGCTCA ATCGACTGAACATAAACCCAGTGACTCTGAGTTCCGGATACAAAGATATTATTCTTTGGTT CAGCTTCGGAGCTTCTTGTTTTGTCCTCCTAGCAGTGGTAATGGGCCTCTTTTTCTTTTGC CTGAAGAACGGAAACATGAGGTGCACAATTTGTATT 859 ATGTACAAAATAGTGGTGATAATCGCCCTTCTCGGCGCAGTGAAAGGGCTCGACAAGATAT GTCTGGGACATCACGCTGTGGCTAATGGCACTATCGTGAAGACGCTCACAAATGAACAGGA GGAGGTTACAAATGCCACTGAGACAGTTGAAAGCACAGGAATCAATAGATTGTGTATGAAA GGCAGAAAGCATAAGGACTTGGGGAACTGTCACCCTATTGGCATGCTTATCGGCACCCCTG CTTGTGATCTACATTTGACAGGCATGTGGGACACCCTTATTGAGCGCGAAAACGCAATCGC GTACTGTTATCCTGGTGCTACTGTGAACGTAGAAGCTCTGAGGCAGAAGATAATGGAATCT GGCGGGATAAATAAAATCTCAACCGGCTTCACATACGGGAGTAGCATTAATAGCGCCGGTA CTACCCGGGCCTGTATGAGGAATGGAGGAAACTCTTTTTACGCAGAGCTCAAGTGGCTAGT ATCTAAGTCCAAGGGACAGAATTTTCCCCAGACTACTAATACTTACCGCAATACGGATACC GCAGAACACTTAATTATGTGGGGCATACATCACCCATCCTCTACCCAAGAAAAGAACGACC TTTACGGCACACAGTCCTTGAGTATATCTGTGGGGAGTAGCACCTATAGGAACAATTTCGT TCCGGTCGTGGGCGCTCGCCCCCAGGTGAACGGCCAATCAGGACGGATCGACTTCCACTGG ACCCTGGTCCAGCCCGGCGATAACATCACATTTTCCCATAACGGAGGACTTATAGCACCCT CCCGGGTGTCTAAACTTATTGGACGGGGGCTGGGAATCCAGTCCGACGCCCCCATCGATAA CAACTGTGAGTCTAAATGTTTTTGGCGCGGCGGATCTATCAACACCAGGCTTCCCTTCCAG AATCTGTCCCCCCGGACAGTGGGCCAGTGCCCAAAGTACGTTAACAGAAGGTCTTTAATGC TCGCCACCGGCATGCGAAACGTGCCTGAACTGATCCAGGGAAGAGGACTTTTCGGAGCCAT CGCCGGCTTTTTAGAGAACGGATGGGAAGGGATGGTAGACGGGTGGTATGGATTCAGGCAC CAAAACGCTCAGGGGACCGGGCAAGCAGCAGACTACAAAAGTACACAAGCCGCTATCGACC AAATCACGGGTAAACTGAACCGGCTTGTGGAAAAGACAAACACCGAATTTGAATCGATAGA GAGCGAATTCAGCGAGATCGAGCACCAAATAGGAAATGTGATCAACTGGACAAAGGATTCG ATCACAGACATCTGGACGTACCAAGCCGAGCTCCTCGTAGCAATGGAGAACCAGCATACCA TCGACATGGCCGATTCCGAGATGCTTAATCTTTATGAACGGGTCCGCAAACAGCTGCGCCA AAATGCCGAAGAAGATGGTAAAGGATGTTTTGAAATCTATCATGCTTGTGATGATTCCTGT ATGGAGTCAATCCGGAATAATACATACGACCACAGCCAGTACCGGGAAGAAGCCCTGCTGA ATCGCTTAAATATCAACCCCGTTACCCTTTCCTCTGGATATAAGGATATTATCCTGTGGTT TTCATTTGGGGCATCCTGTTTCGTCCTTCTGGCAGTGGTCATGGGACTTTTTTTTTTCTGT CTGAAGAACGGAAACATGCGGTGTACGATCTGTATA 860 ATGTATAAAGTCGTGGTTATCATCGCCCTTCTGGGAGCCGTCAGAGGCCTGGACAAGATAT GTTTGGGGCATCATGCGGTAGCTAATGGAACCACTGTCAAAACACTTACTAATGAACAGGA AGAGGTTACGAACGCCACCGAAACAGTGGAATCTACCAGCCTGAATAAATTATGCATGAAG GGACGACGCTACAAGGATCTGGGGAATTGCCACCCCATCGGAATGCTGATTGGAACACCAG TCTGTGACCTCCACCTTACAGGGACGTGGGATACCTTGATTGAGCGGGAGAATGCAACAGC TTACTGTTATCCCGGAGTAACTATTAATGAGGAGGCTCTCCGTCAAAAGATAATGGAGTCA GGAGGTATTAGTAAAATGCGCACTGGCTTTACATACGGGCCCTCTATAAACAGCGCAGGAA CCACTCGTTCATGTATGCGCAATGGGGGCAACTCGTTCTACGCCGAGCTGAAGTGGCTGGT GAGTGGCACCAAAGGTCAGAATTTTCCCCAGACTACAAACACCTACCGGAACACAGACACT GCCGAGCATCTGATCATCTGGGGGATACATCACCCTTCCTCTACTCAAGAAAAGAACGATC TGTATGGCACACAAAGCCTGTCTATATCCGTGGGTTCTTCTACCTATCAAAACAACTTTGT TCCAGTTATAGGCGCCCGGCCCCAGGTGAACGGGCAGTCAGGCCGCATCGAGTTTCACTGG ACTCTGGTCCGGCCCGGAGATAATATTACATTCAGTCATAACGGCGGTTTGATCGCCCCAG ACCGAGTGAGCAAGCTCATCGGGAAGGGGATTGGCATACAATCCGGTGCTGTGATTGACAA GGATTGCGAGAGTAAGTGCTTTTGGCGAGGCGGATCTATTATTACCGAGCTGCCATTTCAG AACCTTTCTCCTCGAACCGTTGGGCAGTGCCCCAAATATGTGAAAAAGAGGTCACTGCTCC TCGCCACTGGCATGCGAAATGTTCCTGAGGTGGTGCAGGGCCGTGGGTTGTTCGGTGCCAT CGCAGGGTTCATCGAGAATGGATGGGAAGGTATGGTCGACGGATGGTACGGATTCCGCCAT CAGAATGCACAGGGTATCGGACAGGCCGCCGATTATAAGAGCACCCAGACGGCTATAGACC AAATCACCGGCAAGCTTAACCGGCTCATAGAAAAGACCAACACAGAATTTGAGTCCATCGA GTCAGAATTCAGCGAAATTGAACATCAGATTGGCAACGTCATCAATTGGACCAAGGACTCC ATCACTGATATCTGGACATACCAGGCAGAACTTTTGGTTGCTATGGAGAACCAACACACCA TAGATATGGCCGATTCCGAGATGTTGAATCTGTACGAGAGGGTCCGTAAGCAGCTGAGGCA GAACGCTGAGGAGGACGGGAAGGGGTGCTTTGAGATCTACCACACCTGTGACAATAGCTGC ATGGAGTCGATCCGGAATAACACTTATGACCATAGTCAATACAGAGAGGAAGCCCTGCTCA ATCGTTTAAATATTAATCCAGTAAAGTTATCTTCAGGGTACAAGGATATTATTCTCTGGTT CTCTTTTGGGGCTAGCTGTTTTGTGCTCCTGGCCGTTATAATGGGACTCGGGTTCTTCTGC CTAAAAAATGGCAACATGCGCTGTACCATTTGCATT 861 ATGTACAAGATTATCGTGATCATCGCACTGCTGGGCGCCGTTAAAGGGCTGGACAAAATAT GCTTGGGACACCACGCCGTAGCTAATGGAACAATCGTCAAAACCCTGACTAATGAGCAAGA GGAGGTCACAAATGCAACGGAAACAGTCGAATCCACTGGCATTAATAGGTTGTGCATGAAG GGCCGAAAGCACAAAGATCTCGGAAATTGTCATCCCATCGGGATGCTGATTGGCACCCCTG CCTGTGATTTGCACTTAACAGGGACTTGGGACACTCTGATAGAGCGTGAAAACGCAATTGC ATATTGCTACCCAGGGGCAACGGTCAACGTGGAGGCTCTCCGACAGAAAATTATGGAAAGC GGAGGGATCGATAAGATTTCGACAGGCTTCACGTACGGCTCCTCAATCAACTCTGCCGGTA CGACGCGCGCGTGTATGCGGAATGGAGGGAACAGCTTTTACGCAGAACTGAAGTGGCTCGT AAGCAAAAGTAAAGGGCAAAATTTCCCTCAGACTACAAATACCTACCGCAACACAGACACA GCGGAGCACCTGATTATGTGGGGAATTCACCATCCCTCAAGTACCCAGGAGAAGAACGACT TATATGGCACGCAGAGTCTTTCCATTTCTGTGGGGTCTAGCACCTATAGGAACAATTTCGT CCCAGTTGTCGGCGCTAGGCCTCAGGTGAATGGACAAAGCGGCCGCATAGATTTCCACTGG ACCCTGGTCCAGCCCGGCGATAATATCACATTTTCTCACAACGGAGGACTGATTGCTCCTA GCAGAGTATCAAAACTGATTGGGAGAGGCCTTGGCATTCAGTCTGACGCCCCCATTGACAA TAATTGTGAGTCTAAGTGTTTTTGGCGGGGAGGAAGCATCAATACCAGACTTCCCTTTCAA AACCTGAGTCCGCGAACTGTCGGACAGTGCCCCAAATACGTTAATAGGCGCTCCCTAATGC TTGCTACAGGTATGAGGAATGTACCAGAGTTAATTCAGGGGCGCGGCCTTTTTGGCGCCAT CGCCGGCTTCCTGGAGAACGGCTGGGAGGGCATGGTGGATGGGTGGTATGGCTTCCGCCAT CAGAACGCACAGGGGACGGGCCAGGCTGCAGATTATAAGTCAACCCAGGCTGCAATAGACC AAATTACTGGGAAGCTGAATAGGCTAGTGGAGAAGACCAACACTGAGTTTGAATCAATTGA GAGCGAATTTAGTGAGATCGAGCACCAGATCGGTAACGTGATTAACTGGACGAAAGATTCA ATTACTGACATTTGGACATATCAGGCTGAGTTGCTGGTGGCGATGGAGAACCAGCACACCA TAGATATGGCGGATAGCGAGATGCTTAATCTGTACGAACGGGTGCGCAAGCAGCTCCGCCA GAACGCTGAAGAAGATGGCAAGGGGTGCTTTGAGATTTACCACGCTTGCGATGATTCATGC ATGGAGTCCATTCGGAATAATACATACGACCACAGTCAGTACAGGGAAGAAGCCCTACTGA ACCGGTTGAACATTAACCCTGTGACCCTCAGTTCAGGGTACAAAGACATAATACTTTGGTT CTCCTTCGGGGCCTCATGTTTCGTGCTGCTGGCAGTCGTTATGGGCCTATTCTTCTTCTGC TTGAAGAATGGAAATATGCGTTGCACCATCTGCATC 862 ATGTACAAAATCGTCGTCATCATTGCACTTCTGGGAGCCGTGAAGGGGCTGGATAAGATCT GCCTCGGCCATCATGCCGTCGTGAACGGTACCATAGTGAAGACATTGACGAACGAGCAAGA GGAAGTCACGAACGCCACCGAGACGGTGGAATCCACGGGACTGAATCGTTTGTGCATGAAA GGCAGGAACCATAAGGATCTGGGAAATTGCCATCCCATAGGCATGCTTATTGGCACGCCAG CCTGTGACCTACACTTAACCGGCACTTGGGACACTTTGATCGAGCGCGAGAATGCCATCGC CTACTGTTATCCAGGAGCCACCGTAAACGAAGAGGCTCTGAGACAGAAGATCATGGAGAGT GGCGGTATAAACAAAATCAGCACCGGCTTCACCTACGGGAGCTCTATCAACTCAGCCGGTA CTACTAGAGCTTGCATGCGCAACGGCGGAAACTCCTTCTACGCAGAACTTAAGTGGCTCGT CAGCAAGAGCAAGGGCCAGAACTTTCCTCAGACAACCAACACCTACCGGAATACCGATACT GCCGAGCACTTGATAATGTGGGGCATCCACCACCCTTCCTCTACTCAGGAAAAGAACGATC TGTATGGTACCCAGTCTCTGTCCATATCAGTGGGTTCTTCAACATACCAGAACAATTTCGT CCCTGTGGTAGGAGCAAGGCCCCAGGTAAATGGCCAGAGCGGCCGCATCGACTTTCATTGG ACTCTGGTGCAGCCAGGGGACAATATTACCTTCAGTCACAACGGCGGCCTGATCGCACCAT CCAGAGTGTCTAAACTGATAGGCCGAGGATTGGGAATTCAGTCAGACGCACCCATAGATAA CAATTGCGAATCGAAGTGTTTCTGGCGCGGCGGCTCAATAAACACCCGACTTCCATTCCAA AACCTCTCTCCCAGAACTGTGGGGCAGTGCCCCAAATACGTGAATAAGAGGTCGCTCATGT TAGCCACTGGTATGCGAAACGTCCCGGAACTGATGCAGGGACGAGGCCTTTTTGGGGCTAT AGCAGGCTTCATCGAGAATGGATGGGAAGGCATGGTTGATGGGTGGTATGGCTTCCGCCAT CAGAATGCTCAGGGGACAGGGCAAGCGGCCGATTACAAATCAACCCAGGCCGCTATAGATC AAATCACTGGCAAGCTGAATCGCCTCATCGAAAAAACAAATACGGAGTTCGAGTCCATTGA AAGCGAGTTTTCCGAGATTGAACACCAAATTGGCAACGTCATAAACTGGACTAAGGACTCT ATTACCGACATATGGACTTACCAGGCAGAGCTTCTGGTCGCTATGGAGAACCAGCACACCA TCGATATGGCCGATTCCGAAATGTTAAACCTCTACGAAAGAGTGCGCAAGCAGCTCAGACA GAACGCCGAAGAAGATGGCAAAGGGTGCTTTGAAATCTACCATGCCTGCGACGATAGTTGT ATGGAGTCGATCCGCAATAACACTTACGATCACAGTCAATATCGGGAGGAGGCACTGTTAA ACAGGCTGAACATTAACCCGGTAACCCTCTCTAGTGGTTACAAAGACATCATACTTTGGTT TTCGTTTGGGGCATCTTGTTTTGTGCTCTTGGCCGTAGTGATGGGACTTGTTTTCTTTTGT CTCAAGAACGGCAATATGCGGTGTACTATTTGCATC 863 ATGTATAAAATCGTCGTGATCATCGCCCTGTTAGGTGCGGTCAAGGGCTTGGACAAGATTT GTCTGGGACATCACGCAGTCGCCAACGGAACCATCGTTAAAACGCTGACTAACGAGCAGGA AAAAGTTACTAATGCCACAGAGACCGTTGAGTCAACCGGCCTCAATAGGCTTTGCATGAAA GGACGGAAGCATAAAGACCTGGGCAACTGCCATCCTATTGGGATGTTAATCGGTACCCCCG CATGCGACCTGCATCTGACTGGAACCTGGGACACCATTATTGAGCGCGAAAATGCCATCGC ATATTGTTACCCCGGAGCTACTGTGAATGAAGAGGCCCTGAGGCAGAAGATCATGGAGTCC GGTGGAATTGACAAGATCTCCACTGGATTTACCTACGGGAGTTCTATCAATAGTGCAGGTA CCACAAGAGCCTGTATGAGAAATGGGGGCAACAGCTTTTACGCCGAATTAAAATGGCTGGT GAGCAAGAGTAAGGGACAAAATTTTCCTCAGACTACAAACACCTACAGAAATACAGATACG GCTGAGCACCTTATCATGTGGGGCATCCACCATCCGTCATCCACCCAAGAGAAGAATGATC TTTACGGAACCCAGAGCTTGAGCATCTCCGTGGGTTCATCCACCTACCGGAACAACTTCGT GCCAGTGGTGGGGGCTAGGCCACAGGTGAACGGCCAGTCAGGCCGCATCGACTTCCACTGG ACACTCGTGCAGCCTGGAGATAACATCACTTTCTCCCACAATGGAGGACTGATAGCCCCAT CTCGCGTTAGCAAGCTGATTGGCCGGGGTCTCGGAATTCAATCTGACGCCCCCATAGACAA TAACTGTGAAAGCAAGTGCTTCTGGCGTGGGGGGTCCATTAATACCCGTCTACCTTTTCAG AATCTGTCCCCCCGCACCGTCGGACAATGCCCTAAGTACGTGAATAAAAGGTCCCTTATGC TAGCTACGGGGATGCGGAATGTTCCGGAGCTAATCCAGGGGCGCGGGCTGTTCGGAGCCAT CGCAGGTTTTCTCGAGAATGGCTGGGAGGGAATGGTGGACGGTTGGTACGGATTCCGCCAC CAGAATGCCCAAGGCACAGGACAGGCAGCTGACTACAAATCAACGCAAGCTGCCATCGACC AGATAACAGGAAAACTGAACAGACTCGTCGAGAAGACCAATACAGAGTTCGAATCCATCGA GTCTGAATTTAGCGAAATCGAGCACCAGATCGGAAACGTTATCAACTGGACAAAAGACTCC ATCACCGATATCTGGACTTACCAGGCTGAACTTCTTGTTGCCATGGAGAATCAGCATACTA TTGATATGGCCGACTCAGAGATGCTCAACCTCTATGAACGGGTCCGGAAACAATTACGACA GAACGCGGAGGAGGACGGCAAAGGTTGCTTTGAGATATATCACGCGTGCGACGATTCGTGC ATGGAATCTATCCGCAATAATACTTACGACCACTCTCAGTACCGGGAGGAAGCACTCCTGA ATCGGTTGAACATCAACCCCGTGACACTTTCTTCCGGCTATAAGGATATAATCCTGTGGTT TTCCTTTGGAGCATCCTGTTTTGTACTCCTCGCCGTAGTGATGGGGCTGGTCTTTTTCTGC CTTAAGAACGGGAACATGAGGTGTACTATATGTATT 864 ATGTACAAGGTGGTGGTCATAATCGCCTTGCTAGGCGCCGTGAGAGGGCTCGACAAAATTT GCTTGGGGCATCATGCAGTCGCTAATGGAACCATCGTGAAAACACTCACCAACGAGCAAGA AGAGGTTACTAACGCCACCGAGACCGTAGAGAGTAAATCCCTGGGGAAGCTGTGTATGAAG GGCCGGTCTTATAATGATCTGGGCAATTGCCATCCCATCGGAATTCTGATCGGGACCCCTG CATGTGATCTGCATCTAACTGGGACGTGGGATACTCTGATCGAGCGCGAGAACGCAGTTGC TTACTGTTATCCGGGCGCCACCGTGAACGAGGAGGCACTCCGACAGAAAATTATGGAATCG GGTGGAATTAGCAAGATATCTACTGGGTTCACCTATGGCACTAGCATCAACTCCGCTGGGA CAACCAAAGCGTGTATGAGAAACGGGGGGAATTCTTTCTACGCCGAACTGAAATGGCTGGT GTCCAAAAATAAAGGGCAGAATTTTCCTCAGACCACCAACACATACCGGAACACCGACACC GCCGAGCACCTGATCATCTGGGGCATTCATCACCCGAGCTCGACTCAAGAGAAGAACGATC TCTACGGGACTCAGTCGCTGAGTATCAGCGTGGGAAGCAGTACTTACCAGAACAATTTTGT ACCCGTGGTGGGAGCCCGGCCTCAAGTCAACGGCCAGTCCGGCAGGATTGACTTCCACTGG ACCTTACTGCAGCCAGGGGACAACATCACCTTTTCACACAATGGTGGACTCATCGCACCCT CCAGAGTTAGCAAACTGATTGGAAGAGGGCTTGGTATTCAGTCGGAAGCCCCTATTGATAA TGGTTGTGAGAGTAAGTGCTTCTGGAAAGGAGGCAGCATAAATACCAAACTCCCCTTCCAG AACCTCTCTCCCAGAACCGTCGGCCAGTGCCCTAAGTACGTGAATAAACGCTCGTTGATGC TCGCGACAGGAATGAGGAACGTGCCTGAAATTATGCATGGTCGCGGACTGTTCGGAGCTAT CGCCGGGTTCATCGAGAATGGCTGGGAAGGGATGGTGGACGGTTGGTACGGGTTTCGACAC CAGAACGCACAGGGCACTGGCCAGGCAGCAGATTATAAGTCCACTCAGGCCGCAATCGACC AGATTACCGGCAAATTAAATAGATTGATCGAGAAAACGAATACTGAGTTCGAGAGCATCGA ATCGGAGTTCTCTGAAATCGAGCATCAGATTGGAAACATTATAAATTGGACCAAGGACAGC ATTACAGATATTTGGACGTATCAGGCAGAGCTGCTGGTGGCCATGGAAAACCAGCATACGA TCGACATGGCCGATTCCGAAATGCTCAACCTGTATGAAAGGGTGAGGAAACAGCTGAGACA AAACGCAGAAGAAGACGGCAAAGGTTGCTTCGAAATTTACCACGCTTGCGACGATTCATGC ATGGAGAGCATTCGGAATAATACCTATGATCATAGCCAGTACAGAGAGGAGGCCCTGCTAA ATAGACTGAATATAAATCCCGTAAAACTGAGCTCTGGCTATAAGGACATTATTCTGTGGTT TAGTTTCGGAGCATCCTGCCTCATCCTCCTGGCAGTGGTCATGGGCCTCGTGTTCTTTTGT CTGAAGAACGGAAATATGCGATGTACTATTTGTATC 865 ATGTACAAAATAGTCGTGATCATCGCACTGCTGGGGGCCGTGAAAGGTCTCGATAAGATTT GCCTTGGACACCATGCCGTGGCTAACGGGACTATTGTGAAGACACTTACCAATGAGCAGGA GGAAGTTACCAACGCTACAGAAACTGTCGAGTCGACTGGTATTAATAGGCTGTGTATGAAG GGACGTAAGCATAAAGACCTCGGGAATTGCCACCCTATAGGCATGCTGATAGGCACCCCAG CATGTGACCTGCACCTCACAGGCATGTGGGACACATTAATCGAAAGGGAGAATGCCATAGC CTATTGCTACCCAGGTGCAACAGTTAATGTTGAAGCATTGCGGCAGAAAATCATGGAGTCC GGCGGCATTAACAAGATCTCTACGGGATTTACGTACGGCTCAAGCATTAATAGTGCCGGGA CTACTCGAGCATGCATGAGGAATGGAGGGAACAGTTTCTACGCCGAGCTGAAGTGGCTCGT GTCTAAAAGTAAAGGGCAGAACTTCCCTCAGACCACTAATACCTACAGAAACACAGACACC GCAGAACACTTAATAATGTGGGGCATACATCACCCCAGCAGCACTCAGGAGAAAAACGACC TGTACGGTACCCAGTCCCTGTCCATTTCCGTGGGAAGTTCTACGTATCGGAATAACTTCGT CCCGGTGGTGGGAGCCAGGCCGCAGGTTAACGGACAAAGCGGGCGAATTGATTTCCACTGG ACACTGGTGCAGCCTGGCGACAATATAACTTTCTCCCATAATGGCGGACTGATCGCTCCAT CCCGGGTCAGCAAGCTAATCGGTAGAGGGCTGGGGATCCAATCAGACGCACCTATTGATAA CAACTGCGAGAGTAAGTGCTTCTGGCGAGGCGGTAGCATAAACACACGTTTGCCATTTCAG AATCTTAGTCCTCGTACTGTGGGCCAATGTCCAAAGTATGTCAACAGGCGCAGTTTAATGT TAGCTACTGGAATGCGCAACGTACCTGAGCTCATTCAAGGTCGAGGCCTGTTCGGAGCCAT TGCTGGGTTCCTTGAGAATGGGTGGGAGGGCATGGTCGACGGATGGTACGGATTCCGCCAC CAGAACGCCCAGGGCACAGGCCAGGCAGCCGATTATAAAAGTACCCAGGCTGCCATCGACC AGATCACTGGGAAACTCAACCGTCTGGTCGAAAAGACTAACACCGAATTTGAGTCTATTGA ATCAGAATTCAGCGAAATTGAGCACCAGATCGGCAATGTGATCAATTGGACGAAAGACTCT ATTACCGACATTTGGACCTACCAGGCCGAGTTACTGGTGGCCATGGAGAACCAGCACACCA TCGACATGGCCGATAGTGAAATGCTTAACCTCTACGAAAGAGTCCGAAAACAACTCCGCCA GAACGCGGAGGAGGATGGAAAGGGCTGCTTCGAAATCTATCATGCCTGCGACGACTCCTGT ATGGAAAGCATTCGCAACAACACCTACGACCACAGTCAGTACAGGGAGGAGGCGCTGCTTA ATAGGCTGAACATCAATCCGGTAACACTGTCATCGGGATACAAGGACATCATACTCTGGTT CTCATTCGGCGCGTCCTGTTTCGTACTGCTCGCAGTCGTAATGGGGCTCTTCTTCTTCTGC TTAAAGAACGGCAACATGCGCTGCACTATCTGCATT 866 ATGTATAAAATTGTGGTCATAATTGCACTGCTCGGCGCAGTCAAGGGTCTGGATAAGATTT GCCTTGGTCACCATGCCGTAGCCAACGGAACCATTGTGAAGACCCTTACAAATGAACAAGA AGAAGTGACTAATGCAACTGAGACCGTGGAATCTACAGGTATCAATCGCCTGTGTATGAAG GGGCGAAAACATAAAGATCTCGGCAATTGTCACCCCATTGGGATGCTGATTGGCACCCCGG CATGTGACCTACATTTGACCGGAATGTGGGATACACTAATCGAACGGGAGAATGCTATTGC GTACTGTTACCCTGGCGCTACCGTCAATGTGGAGGCCCTGCGCCAAAAAATCATGGAATCT GGGGGAATCAATAAGATCTCCACTGGCTTCACTTATGGATCCAGCATTAACAGCGCTGGCA CAACTCGCGCCTGTATGCGCAATGGGGGCAATTCCTTCTATGCAGAGCTTAAGTGGTTAGT GAGCAAGTCGAAAGGCCAAAACTTCCCTCAAACAACCAATACATATAGGAACACCGATACC GCTGAACATCTCATTATGTGGGGAATACATCATCCCAGCTCCACACAAGAGAAGAATGATT TGTACGGGACCCAATCCTTGTCTATTAGCGTAGGCTCCTCCACATACCGGAACAACTTCGT CCCAGTCGTGGGGGCACGGCCTCAGGTTAACGGACAGTCCGGCCGTATTGACTTCCACTGG ACTCTGGTGCAACCAGGGGACAACATCACTTTCTCTCATAACGGGGGTCTGATCGCACCTA GTAGGGTGTCCAAACTTATAGGAAGGGGTCTCGGCATCCAAAGCGACGCCCCCATCGATAA TAATTGCGAAAGCAAGTGTTTTTGGAGGGGAGGGAGCATCAATACTCGGTTACCATTTCAG AATTTAAGTCCAAGAACAGTAGGACAATGCCCTAAGTATGTTAATAGACGTTCCCTCATGT TAGCAACTGGAATGAGGAACGTTCCGGAGCTGATTCAGGGAAGAGGACTCTTCGGGGCAAT CGCCGGTTTTTTGGAGAACGGATGGGAGGGCATGGTGGATGGTTGGTACGGATTCCGCCAT CAGAACGCCCAGGGCACCGGGCAAGCTGCAGACTATAAATCAACACAAGCAGCAATTGATC AAATCACCGGCAAGTTGAACAGGCTGGTCGAGAAAACCAACACTGAATTCGAGTCCATCGA GAGCGAGTTCTCTGAAATAGAGCATCAGATTGGAAACGTTATCAACTGGACCAAGGATAGT ATCACGGACATTTGGACTTATCAAGCCGAGCTGCTGGTCGCCATGGAGAATCAACATACTA TCGACATGGCGGATAGTGAAATGCTCAACCTGTACGAGCGCGTGCGCAAGCAACTGCGCCA GAACGCTGAAGAGGACGGTAAAGGTTGCTTTGAAATTTATCACGCTTGTGATGACTCCTGC ATGGAGTCGATCCGCAATAATACGTACGATCACAGCCAGTACCGGGAGGAGGCTTTGCTGA ACCGGCTGAACATCAACCCTGTAACCTTGTCTTCTGGCTACAAGGATATTATACTCTGGTT CAGCTTCGGCGCCAGCTGCTTCGTCCTGCTGGCCGTGGTTATGGGACTCTTCTTTTTCTGT CTGAAAAATGGTAATATGCGGTGCACAATTTGTATC 867 ATGTACAAGATTGTGGTAATCATCGCTTTACTTGGGGCAGTGAAAGGATTGGACAAGATTT GTTTGGGGCACCATGCAGTGGCCAACGGCACCATTGTTAAAACACTGACAAATGAGCAGGA AGAGGTTACCAATGCAACGGAAACCGTGGAATCTACTGGAATCAACAGACTGTGCATGAAG GGCCGCAAGCATAAAGACTTGGGGAATTGCCACCCAATTGGAATGCTTATTGGAACACCAG CTTGCGATTTACATCTGACTGGCATGTGGGACACCCTCATCGAGCGGGAAAATGCTATCGC TTATTGCTACCCGGGGGCCACAGTGAATGTGGAAGCACTACGGCAAAAAATCATGGAATCA GGCGGAATCAACAAAATCTCAACCGGCTTCACCTATGGGTCATCCATCAATAGTGCTGGCA CCACACGCGCCTGCATGCGAAATGGTGGAAACTCATTCTATGCGGAACTGAAATGGCTAGT GTCAAAAAGCAAAGGGCAGAATTTTCCACAGACTACGAACACTTATAGAAATACTGACACA GCTGAGCATCTTATTATGTGGGGCATCCATCATCCAAGCAGTACACAGGAAAAGAATGACC TATACGGTACACAGTCCCTGTCTATTTCCGTGGGATCCTCCACATACAGAAACAACTTTGT CCCTGTGGTGGGAGCAAGGCCTCAGGTCAACGGACAGTCTGGCCGCATCGATTTCCATTGG ACCCTGGTTCAACCGGGCGATAACATCACCTTCAGCCACAATGGAGGCCTGATCGCCCCTA GCAGGGTGTCAAAGCTTATAGGCAGGGGTCTTGGGATCCAATCCGACGCCCCCATAGACAA TAACTGCGAGTCGAAATGTTTCTGGCGGGGTGGTTCCATTAATACTCGTCTCCCCTTCCAG AATCTTTCTCCCAGAACTGTTGGGCAATGCCCCAAGTACGTAAATCGTAGAAGTCTTATGC TCGCAACCGGTATGCGCAACGTGCCTGAGCTCATTCAGGGCCGGGGCCTCTTTGGGGCTAT TGCCGGCTTCCTTGAAAACGGCTGGGAGGGTATGGTGGATGGCTGGTACGGATTCCGCCAC CAGAATGCCCAAGGCACAGGTCAGGCTGCCGACTATAAGTCAACGCAGGCTGCCATCGATC AGATCACAGGCAAGTTGAACAGGCTAGTGGAGAAGACCAACACAGAGTTTGAGAGTATTGA GAGCGAGTTTTCCGAAATCGAACACCAGATAGGCAACGTTATCAACTGGACAAAGGACAGT ATTACAGACATTTGGACATATCAGGCTGAACTGTTGGTGGCCATGGAGAACCAGCACACTA TCGATATGGCAGACTCCGAGATGCTGAATTTGTACGAAAGGGTCCGGAAGCAGCTCCGCCA GAACGCCGAAGAGGATGGGAAAGGCTGCTTTGAAATTTACCACGCTTGCGACGACTCCTGT ATGGAATCCATTCGAAATAATACATATGATCACAGCCAGTACCGGGAAGAAGCTTTACTTA ATCGATTGAATATCAATCCAGTTACCCTTTCCTCCGGCTACAAGGACATCATTCTGTGGTT CTCCTTCGGTGCCTCGTGCTTCGTCCTGCTTGCAGTTGTTATGGGGCTGTTTTTTTTCTGT CTGAAGAACGGGAATATGCGGTGCACTATTTGCATC 868 ATGTATAAAATCGTGGTTATCATCGCCCTGTTGGGCGCAGTCAAAGGCTTAGACAAAATTT GCCTGGGCCACCATGCCGTGGCCAATGGCACAATTGTAAAAACTTTGACTAATGAGCAGGA GGAAGTCACTAACGCCACGGAAACCGTGGAGTCCACTGGAATCAACCGCCTGTGCATGAAG GGACGGAAGCATAAGGACCTCGGTAATTGTCATCCGATAGGTATGCTCATCGGCACCCCCG CTTGCGACTTACATTTGACAGGAATGTGGGACACTCTGATTGAGAGGGAGAACGCCATTGC CTACTGTTACCCCGGCGCAACAGTCAATGTGGAGGCGCTGCGTCAAAAGATAATGGAGAGT GGAGGCATCAACAAAATTTCAACAGGGTTCACATACGGGAGCTCAATTAACTCTGCGGGCA CGACCAGGGCTTGCATGAGAAACGGCGGTAATTCCTTTTATGCGGAGTTGAAATGGCTGGT CTCCAAGTCCAAGGGTCAGAATTTCCCACAAACCACAAATACTTACCGAAATACGGACACT GCCGAGCATCTGATAATGTGGGGAATACACCATCCTAGTTCTACGCAAGAGAAAAATGACC TCTATGGGACGCAATCCTTGAGTATCAGCGTTGGCTCCTCAACCTACCGGAACAACTTCGT CCCAGTTGTAGGAGCTCGACCTCAGGTGAATGGACAGTCAGGTCGTATCGATTTTCATTGG ACCCTCGTGCAACCTGGGGACAACATAACCTTCTCCCACAACGGCGGGCTGATAGCACCCA GTCGTGTCTCCAAATTGATCGGGAGGGGGCTGGGCATCCAATCAGATGCACCAATTGATAA TAATTGTGAGAGCAAGTGCTTCTGGCGTGGGGGTAGCATCAACACTCGCCTCCCCTTTCAG AACTTGTCACCCCGGACCGTCGGTCAGTGTCCCAAGTATGTTAATCGGCGTTCATTAATGC TGGCAACCGGTATGCGCAACGTCCCCGAGCTAATCCAAGGAAGAGGGCTTTTTGGGGCTAT AGCAGGATTTTTAGAGAACGGTTGGGAGGGCATGGTGGACGGATGGTACGGCTTTCGGCAC CAGAATGCGCAGGGGACAGGGCAAGCTGCCGATTATAAGTCCACTCAAGCTGCTATTGATC AGATTACAGGCAAGCTTAATCGCCTGGTCGAGAAGACTAACACAGAGTTCGAGAGCATTGA GTCAGAATTCTCTGAAATTGAGCACCAAATCGGGAATGTAATAAATTGGACAAAGGACAGT ATTACCGACATCTGGACTTATCAAGCCGAGCTCCTGGTTGCTATGGAGAATCAGCACACAA TCGACATGGCCGATAGCGAGATGCTAAACCTGTACGAAAGGGTGCGCAAGCAGCTGAGGCA AAACGCTGAGGAAGATGGCAAGGGCTGTTTCGAGATTTATCACGCGTGTGATGATTCATGC ATGGAATCAATTAGGAACAACACTTACGATCATTCTCAGTACCGGGAGGAGGCACTCCTGA ACAGGCTCAACATAAACCCTGTCACCCTGTCTTCAGGCTATAAGGACATTATACTATGGTT TTCTTTTGGCGCCTCCTGTTTTGTGCTCCTCGCCGTTGTAATGGGCCTTTTTTTTTTTTGC CTGAAGAACGGTAATATGCGGTGTACTATTTGCATT 869 ATGTACAAGATTGTAGTGATTATCGCACTGCTAGGCGCGGTGAAGGGTCTCGACAAGATTT GCCTGGGCCATCACGCGGTGGCCAACGGGACTATCGTGAAGACTCTGACCAATGAACAAGA GGAAGTTACTAACGCCACCGAAACTGTGGAGTCCACAGGCATCAATCGCTTGTGTATGAAG GGAAGGAAGCATAAAGACCTGGGTAATTGTCACCCCATAGGGATGCTTATCGGTACACCAG CTTGTGATCTGCATTTAACGGGGATGTGGGACACACTTATAGAACGTGAGAATGCCATTGC CTATTGTTACCCCGGAGCTACCGTAAACGTGGAGGCCCTGCGCCAGAAGATCATGGAGTCA GGGGGCATCAATAAGATCAGTACCGGCTTTACCTATGGTAGCTCTATCAACTCCGCCGGCA CTACCAGGGCCTGTATGAGGAATGGGGGAAACAGCTTCTATGCTGAGCTGAAGTGGCTAGT TAGCAAGAGCAAGGGCCAGAACTTCCCTCAAACTACAAATACGTATCGGAACACCGACACA GCGGAGCACCTGATAATGTGGGGAATCCACCACCCATCGTCCACCCAAGAAAAGAACGATC TGTACGGTACTCAGTCCCTGAGTATTTCCGTGGGCTCCAGTACGTACCGAAATAATTTCGT CCCAGTGGTCGGGGCAAGGCCGCAAGTGAATGGCCAGTCAGGACGGATAGACTTTCATTGG ACACTGGTGCAACCCGGCGATAACATCACCTTCAGCCATAACGGGGGGCTGATCGCCCCGA GCCGAGTTAGCAAACTTATCGGCCGGGGCCTGGGCATCCAGAGTGATGCACCCATCGACAA TAATTGCGAGAGCAAATGTTTTTGGAGGGGTGGATCGATAAACACACGCCTCCCGTTCCAA AATCTCAGTCCTAGAACAGTGGGGCAGTGTCCTAAGTATGTGAATCGCCGGAGCCTTATGT TGGCCACTGGGATGCGAAATGTGCCCGAACTAATTCAAGGGCGAGGACTGTTCGGCGCCAT TGCCGGCTTCCTGGAGAATGGCTGGGAAGGCATGGTTGATGGTTGGTATGGCTTTCGCCAT CAGAATGCACAGGGGACAGGCCAGGCCGCGGATTACAAATCGACCCAAGCTGCAATTGATC AGATCACAGGGAAACTGAATCGACTTGTGGAGAAAACTAATACCGAATTTGAATCTATCGA GTCCGAATTTAGCGAAATCGAGCACCAGATCGGTAACGTGATCAATTGGACTAAGGACTCC ATTACAGACATATGGACATATCAGGCCGAGTTGTTGGTGGCAATGGAGAACCAGCATACTA TCGACATGGCCGATTCTGAGATGCTAAATCTGTATGAACGCGTCCGGAAACAGCTCAGACA GAATGCTGAGGAAGATGGGAAGGGATGCTTCGAAATATACCACGCCTGCGACGACAGCTGT ATGGAGTCAATTCGCAACAACACTTACGATCACTCCCAATACCGGGAGGAGGCCCTTCTTA ACAGACTCAACATTAATCCTGTGACTCTGTCATCCGGATACAAAGACATAATACTCTGGTT TAGCTTTGGCGCAAGTTGTTTTGTGCTGCTCGCAGTGGTGATGGGGTTGTTTTTTTTCTGC CTGAAAAATGGTAATATGCGATGCACTATCTGCATC 870 ATGTACAAAATTGTGGTGATAATTGCATTGCTCGGAGCAGTCAAAGGGCTGGACAAAATAT GTTTGGGGCACCACGCCGTGGTTAATGGTACCATCGTTAAGACTCTGACCAACGAACAGGA AGAGGTGACCAATGCTACCGAGACCGTGGAAAGCACTGGGTTGAACAGGCTGTGCATGAAA GGAAGGAATCACAAGGACCTGGGAAACTGTCATCCAATCGGAATGCTCATTGGGACTCCCG CATGTGATCTGCATCTGACGGGCACCTGGGATACCTTGATAGAGAGGGAGAACGCCATAGC ATACTGTTATCCCGGAGCCACCGTGAACGAGGAGGCACTGAGGCAGAAAATTATGGAATCT GGAGGGATCAATAAAATTAGCACAGGGTTTACCTATGGCTCAAGTATCAATAGCGCCGGGA CTACACGGGCCTGCATGCGAAATGGAGGGAACTCCTTCTACGCTGAACTAAAGTGGCTGGT CAGTAAGTCCAAAGGGCAGAATTTCCCGCAGACAACCAACACTTACCGCAATACCGATACG GCTGAACACTTAATCATGTGGGGCATCCATCATCCCTCTAGCACACAAGAGAAAAACGACC TGTATGGAACACAAAGCCTCAGCATCTCCGTGGGTTCATCTACATATCAGAACAACTTCGT GCCCGTCGTTGGCGCCCGACCTCAGGTGAATGGTCAATCGGGCCGGATTGACTTTCACTGG ACCCTCGTCCAGCCAGGTGATAACATCACCTTCAGCCACAACGGCGGACTCATCGCCCCAT CTCGTGTGTCCAAGCTCATTGGCAGAGGGCTTGGCATCCAGTCTGATGCACCCATCGATAA CAATTGCGAGAGCAAGTGTTTCTGGCGCGGTGGATCAATAAATACGCGGCTCCCCTTTCAG AATCTTTCTCCCAGAACCGTAGGCCAGTGTCCAAAGTATGTAAACAAAAGATCATTGATGC TGGCCACAGGAATGAGGAATGTGCCTGAGCTGATGCAGGGCAGAGGCCTGTTCGGTGCGAT CGCCGGCTTCATCGAAAATGGCTGGGAGGGGATGGTGGACGGATGGTATGGCTTCCGCCAC CAGAACGCTCAGGGGACCGGACAAGCTGCGGATTATAAGAGCACTCAGGCGGCAATCGACC AGATCACCGGAAAACTCAACCGTCTCATCGAGAAGACAAACACCGAATTTGAGTCTATAGA ATCTGAGTTCAGTGAAATCGAACACCAAATCGGCAACGTCATAAATTGGACTAAGGACTCC ATCACCGATATCTGGACCTATCAAGCCGAGCTGCTGGTTGCCATGGAGAATCAGCACACGA TCGACATGGCTGATTCTGAAATGCTGAACCTCTATGAAAGAGTTCGGAAACAGCTCAGACA AAACGCCGAAGAGGACGGCAAAGGATGTTTTGAGATCTATCATGCCTGCGATGATAGTTGT ATGGAGAGCATCAGGAATAATACATACGACCACTCCCAGTATCGCGAGGAAGCACTGCTCA ATCGGTTAAATATAAATCCAGTGACGCTTAGTAGTGGGTATAAGGACATAATCCTCTGGTT CTCTTTCGGCGCCAGCTGTTTCGTTCTGCTGGCCGTGGTCATGGGACTTGTGTTCTTTTGT CTTAAAAATGGGAACATGAGATGCACAATATGTATT 871 ATGTATAAAATAGTGGTGATAATCGCGCTACTGGGCGCAGTGAAGGGGCTCGATAAGATTT GCTTGGGTCATCATGCTGTTGCAAACGGCACCATCGTTAAAACACTGACCAACGAGCAGGA GGAGGTAACGAACGCCACGGAGACGGTGGAGTCTACCGGGATCAACCGTCTGTGTATGAAG GGTCGCAAGCATAAGGATTTAGGAAATTGTCATCCTATCGGAATGCTTATAGGTACCCCGG CCTGCGATCTCCATCTGACAGGCATGTGGGATACTCTCATCGAAAGAGAGAATGCCATCGC GTATTGTTACCCTGGGGCCACAGTAAATGTCGAAGCATTGAGACAGAAAATCATGGAGTCC GGAGGCATTAATAAGATTTCCACCGGCTTCACCTACGGATCTTCCATCAATTCCGCAGGCA CAACCAGAGCCTGCATGCGGAATGGAGGGAATTCCTTTTACGCCGAATTGAAATGGCTTGT GTCAAAGTCAAAGGGACAGAACTTTCCCCAAACTACGAACACATATAGAAATACAGATACC GCAGAACACTTAATTATGTGGGGCATCCACCACCCGTCAAGTACTCAGGAGAAGAATGACC TTTACGGCACCCAGTCTCTTTCAATCTCAGTCGGGAGCTCCACATATAGAAACAACTTTGT ACCTGTGGTCGGTGCAGGACCGCAGGTGAATGGCCAATCAGGAAGGATCGATTTTCACTGG ACACTGGTCCAGCCTGGTGACAACATCACGTTCTCACACAATGGGGGCCTAATAGCCCCCT CCCGCGTGAGCAAGCTAATTGGCCGCGGATTGGGTATCCAGAGCGACGCCCCTATAGACAA TAACTGTGAGAGCAAGTGCTTCTGGCGCGGAGGGTCAATTAACACCCGGCTCCCCTTCCAG AACCTGTCCCCCCGGACGGTGGGCCAGTGCCCAAAATACGTCAATCGGCGCTCCCTGATGT TGGCCACAGGCATGCGGAATGTTCCTGAACTGATACAGGGTCGGGGGTTGTTCGGAGCAAT TGCCGGGTTTCTTGAAAACGGCTGGGAAGGTATGGTGGATGGTTGGTACGGGTTCAGGCAC CAGAACGCTCAGGGTACCGGCCAGGCGGCTGACTACAAATCAACCCAGGCAGCAATCGACC AGATTACAGGAAAGCTGAATCGCCTTGTGGAGAAAACCAATACCGAATTTGAGTCCATCGA GTCTGAGTTCAGCGAGATAGAGCATCAGATTGGCAACGTCATCAACTGGACGAAGGACTCC ATTACTGATATATGGACTTATCAGGCTGAACTGCTGGTAGCCATGGAGAACCAGCACACAA TTGACATGGCTGACTCCGAGATGCTGAATCTATACGAGCGCGTGAGGAAGCAGCTCAGACA GAACGCTGAGGAGGACGGTAAGGGTTGCTTCGAGATTTACCACGCCTGTGATGACTCCTGT ATGGAGTCAATCAGGAACAATACCTATGACCACTCTCAATATCGGGAGGAAGCGCTTCTCA ACCGTCTTAACATTAATCCCGTGACACTGTCTTCAGGTTACAAGGATATCATCCTGTGGTT CAGCTTTGGCGCCAGCTGTTTCGTGCTACTAGCAGTGGTGATGGGCCTGTTTTTTTTCTGC CTGAAAAATGGGAACATGAGGTGCACGATTTGCATC 872 ATGTATAAAATCGTTGTAATTATTGCACTGCTTGGCGCCGTGAAGGGACTCGACAAGATCT GCCTGGGCCACCACGCTGTAGCCAACGGCACCATTGTGAAGACCCTGACAAATGAGCAGGA GGAGGTTACCAATGCCACTGAGACCGTGGAATCCACAGGCATTAACCGCCTGTGTATGAAG GGAAGGAAGCACAAGGACCTTGGCAATTGTCACCCAATCGGCATGCTCATCGGCACACCAG CATGCGACTTGCACCTGACCGGAATGTGGGACACGCTCATAGAAAGAGAGAATGCCATTGC CTATTGCTACCCAGGAGCCACCGTTAACGTGGAGGCACTGAGGCAGAAGATCATGGAGAGC GGAGGCATCAATAAAATTAGTACGGGGTTTACATATGGCTCCTCTATAAATTCCGCCGGCA CCACCCGGGCCTGCATGCGGAATGGCGGAAATAGTTTCTACGCTGAGTTGAAATGGCTGGT GAGCAAGAGTAAGGGGCAGAACTTTCCGCAAACTACCAATACGTATAGGAACACTGACACC GCCGAGCACCTAATCATGTGGGGCATACATCATCCCAGCTCCACGCAGGAGAAGAACGACC TGTATGGAACTCAAAGCCTATCTATCTCCGTGGGATCCAGTACATACCGGAATAACTTTGT GCCAGTAGTGGGCGCCAGACCGCAGGTGAACGGGCAATCCGGCAGGATCGACTTCCACTGG ACACTGGTGCAACCAGGCGACAACATTACTTTCAGCCACAATGGTGGTTTAATAGCCCCCT CAAGGGTTTCCAAATTGATTGGGCGGGGGCTTGGTATTCAATCTGACGCTCCAATAGATAA CAATTGTGAAAGTAAGTGTTTCTGGCGCGGCGGCTCTATTAATACTCGCCTTCCATTCCAA AATCTCTCACCACGTACCGTTGGCCAATGTCCCAAATATGTGAACCGTAGGTCCTTGATGC TCGCAACGGGAATGAGGAACGTTCCGGAGCTGATCCAGGGCCGAGGACTCTTTGGTGCTAT TGCCGGATTTCTGGAGAACGGGTGGGAGGGCATGGTGGATGGATGGTACGGCTTCCGACAT CAGAATGCACAAGGCACCGGGCAGGCCGCCGATTACAAGTCCACGCAAGCTGCCATTGACC AGATTACGGGGAAGTTGAACCGGCTCGTCGAGAAGACCAATACTGAATTCGAATCCATTGA GAGCGAATTTTCTGAAATTGAACATCAGATTGGTAACGTCATCAATTGGACTAAGGACTCA ATAACAGACATCTGGACTTATCAGGCTGAACTCCTCGTCGCGATGGAAAATCAGCACACCA TCGATATGGCCGACTCTGAGATGCTGAACTTGTACGAGCGGGTGAGAAAACAGCTTCGACA GAATGCCGAGGAAGATGGCAAGGGCTGCTTCGAGATCTATCACGCTTGCGATGACTCATGC ATGGAGTCTATCCGGAACAACACTTATGACCACTCCCAATACCGCGAGGAGGCCCTGCTGA ATAGGCTGAACATCAACCCAGTGACCTTGAGCTCAGGCTATAAGGACATAATCCTGTGGTT TAGCTTTGGGGCCTCGTGCTTTGTCCTGCTGGCCGTAGTTATGGGGCTTTTCTTCTTTTGT CTTAAGAATGGGAATATGAGGTGTACAATCTGTATC 873 ATGTACAAGATCGTGGTTATCATCGCACTCCTCGGGGCTGTGAAGGGTCTCGACAAAATCT GCCTTGGTCATCACGCAGTTGCCAACGGAACTATTGTTAAGACCTTGACTAATGAGCAGGA GGAGGTGACAAACGCCACAGAAACCGTGGAAAGTACGGGGATCAACCGTTTATGCATGAAG GGAAGGAAACACAAAGATCTCGGTAACTGCCATCCGATCGGTATGCTCATTGGCACTCCAG CTTGCGACTTGCACTTGACCGGTATGTGGGACACATTAATTGAACGCGAGAACGCCATCGC CTATTGCTACCCCGGAGCCACTGTGAACGTGGAAGCACTCCGACAGAAAATAATGGAAAGT GGGGGGATAAATAAGATCTCAACCGGATTTACATACGGTTCCTCAATTAATAGCGCCGGGA CCACTAGAGCATGCATGCGAAATGGAGGTAATTCTTTTTACGCTGAGCTTAAATGGCTGGT GTCTAAAAGCAAGGGCCAGAATTTTCCACAGACGACGAACACTTATAGGAATACAGACACA GCCGAACACCTGATCATGTGGGGAATCCACCACCCATCTAGCACACAGGAGAAAAACGACC TATATGGTACCCAAAGCCTGTCAATTAGCGTCGGCAGTAGTACATACCGCAATAATTTCGT TCCCGTTGTCGGAGCCAGGCCGCAAGTGAACGGGCAAAGTGGCAGAATTGATTTCCACTGG ACACTGGTCCAGCCCGGGGATAACATTACATTCAGCCACAACGGCGGGCTTATCGCCCCCT CCCGTGTGAGTAAGCTGATCGGCCGGGGCTTAGGTATCCAGTCCGATGCTCCCATCGACAA CAATTGTGAATCGAAGTGCTTTTGGCGGGGCGGCTCCATCAATACCCGGCTGCCTTTCCAG AACCTGAGCCCCAGGACCGTTGGACAGTGTCCCAAATACGTTAACCGGCGGAGTCTGATGC TTGCAACCGGGATGCGCAATGTGCCCGAACTGATCCAGGGGCGAGGACTGTTCGGGGCCAT CGCCGGATTCCTGGAGAATGGCTGGGAGGGTATGGTGGACGGCTGGTACGGCTTTAGGCAC CAAAATGCTCAAGGAACAGGGCAGGCTGCTGACTACAAATCAACCCAGGCCGCTATTGATC AAATTACTGGAAAGCTGAATAGATTGGTGGAGAAAACTAATACTGAATTCGAGTCCATCGA AAGTGAGTTCAGCGAGATCGAGCACCAGATTGGTAACGTTATTAACTGGACCAAAGACAGC ATCACCGACATTTGGACCTACCAGGCCGAGCTTCTAGTAGCCATGGAAAATCAACACACGA TCGATATGGCTGATTCAGAGATGCTGAATCTGTATGAGCGGGTCCGGAAACAGCTGAGACA GAATGCAGAGGAAGACGGTAAGGGGTGTTTTGAGATTTACCATGCCTGCGATGATTCTTGC ATGGAATCTATCAGGAACAACACCTATGACCACTCCCAATATCGCGAGGAGGCCCTGCTGA ACAGGTTAAACATCAACCCCGTCACCCTGTCTTCAGGATATAAAGACATCATCTTATGGTT CTCCTTCGGAGCGTCCTGTTTTGTGCTGTTGGCAGTGGTCATGGGGCTTTTCTTTTTCTGT CTAAAAAACGGTAACATGCGGTGCACCATATGCATC 874 ATGTATAAAATTGTAGTTATTATCGCCCTGTTGGGCGCTGTGAAGGGCTTGGACAAGATCT GCCTGGGACACCATGCAGTCGCAAATGGAACAATTGTCAAGACACTGACTAATGAGCAGGA AGAGGTTACCAACGCCACAGAGACCGTAGAGTCCACCGGGATTAATCGGCTATGCATGAAA GGAAGAAAGCACAAAGATCTCGGGAACTGTCATCCAATTGGTATGCTGATCGGAACCCCCG CCTGTGATCTCCATCTTACTGGCACTTGGGACACCTTGATTGAGAGGGAAAACGCCATTGC TTATTGTTACCCAGGAGCTACCGCCAACGTCGAGGCCCTAAGGCAGAAGATCATGGAGTCT GGAGGAATTGATAAGATCTCAACGGGGTTTACATACGGGTCTAGTATCAATAGCGCAGGCA CTACCCGCGCTTGTATGAGGAACGGCGGCAACTCGTTTTACGCCGAGTTGAAATGGCTGGT CAGTAAATCAAAGGGGCAGAATTTTCCACAGACCACAAACACTTATAGGAATACCGATACA GCTGAACACCTCATCATGTGGGGCATCCATCACCCCAGCTCCATTCAAGAGAAGAACGACT TGTATGGCACACAGTCATTGAGCATCAGTGTGGGCAGCAGCACATACAGAAACAACTTCGT GCCCGTGGTTGGGGCAAGACCTCAGGTAAACGGCCAGTCCGGTAGGATTGACTTCCATTGG ACGCTCGTGCAACCGGGAGATAACATCACCTTCAGCCACAATGGGGGACTCATCGCACCCT CTCGAGTTAGCAAACTGATCGGGCGAGGCTTAGGCATACAATCCGACGCGCCTATCGATAA CAATTGCGAATCCAAATGTTTCTGGCGCGGCGGTAGCATTAATACTCGTCTGCCATTCCAG AACCTTAGCCCCAGGACAGTGGGACAGTGTCCAAAATACGTGAATCGCAGAAGTCTCATGC TGGCTACCGGCATGAGGAACGTGCCAGAGCTTATACAGGGGCGGGGCTTGTTCGGAGCGAT CGCTGGCTTCTTGGAGAATGGCTGGGAGGGCATGGTCGACGGATGGTATGGTTTTCGACAT CAAAACGCCCAGGGCACGGGGCAGGCCGCCGATTACAAGTCCACTCAGGCAGCAATCGACC AGATCACCGGTAAGCTTAATAGACTGGTCGAGAAGACAAATACCGAGTTCGAATCTATTGA ATCCGAGTTCAGCGAAATCGAACACCAAATAGGGAACGTCATCAACTGGACCATGGACAGC ATCACCGATATATGGACATATCAGGCTGAGTTGCTTGTGGCCATGGAAAATCAGCACACAA TCGATATGGCTGATTCCGAAATGCTGAACCTGTACGAACGGGTAAGGAAGCAGCTGCGGCA GAACGCAGAAGAGGATGGGAAGGGCTGCTTCGAAATTTACCACGCTTGTGATGACTCTTGT ATGGAGTCTATTCGCAACAACACCTACGACCATTCTCAGTATCGTGAGGAGGCCCTTCTCA ATCGTCTGAACATCAATCCGGTGACCCTATCTTCAGGATATAAGGATATTATACTCTGGTT CTCCTTCGGGGCAAGCTGCTTCGTCTTGCTGGCCGTCGTCATGGGGCTGGTTTTCTTCTGT TTAAAAAATGGAAATATGAGGTGCACCATTTGTATC 875 ATGTACAAGATTGTAGTTATTATCGCTTTACTGGGAGCGGTCAAAGGTCTGGACAAGATAT GCCTTGGACACCACGCAGTGGCTAACGGCACAATCGTCAAAACTCTGACAAACGAGCAGGA GGAGGTCACTAATGCGACCGAAACGGTGGAGAGCACCGGAATTAATCGACTATGTATGAAG GGCAGGAAGCACAAGGATCTCGGGAACTGCCATCCCATCGGCATGCTGATAGGCACGCCAG CCTGCGATCTTCATCTGACCGGAATGTGGGATACCCTGATCGAGAGAGAAAACGCCATTGC ATACTGTTACCCGGGAGCAACCGTCAATGTGGAGGCGCTGAGACAGAAAATTATGGAAAGC GGAGGGATCAATAAAATCAGTACCGGGTTTACTTATGGCTCATCAATCAATTCAGCAGGCA CTACTAGAGCTTGCATGAGGAATGGAGGGAATAGTTTCTACGCGGAGTTGAAATGGCTCGT GAGTAAATCTAAGGGGCAGAATTTTCCCCAGACTACAAATACGTATAGAAACACCGATACT GCCGAGCACTTAATCATGTGGGGCATCCATCATCCAAGCAGTACCCAGGAGAAAAACGACC TCTATGGGACTCAGTCCTTGAGCATTAGCGTCGGATCTTCCACATACAGAAACAATTTCGT TCCAGTCGTCGGAGCTCGACCTCAGGTTAACGGGCAATCCGGGCGAATAGACTTTCATTGG ACTCTGGTGCAGCCCGGGGACAACATAACCTTCAGTCACAATGGAGGGCTGATAGCCCCCA GTCGCGTGAGTAAATTGATTGGCAGGGGCCTAGGAATCCAATCTGACGCACCCATCGACAA CAACTGCGAGAGCAAATGCTTTTGGCGCGGTGGGTCAATAAACACTCGCCTCCCTTTTCAG AATTTGTCACCTCGGACAGTGGGACAGTGCCCTAAGTATGTGAATCGCCGATCCCTGATGC TAGCCACCGGCATGCGCAATGTGCCCGAGCTGATTCAGGGAAGGGGCCTGTTCGGCGCCAT CGCCGGCTTCTTGGAAAATGGCTGGGAGGGGATGGTTGACGGCTGGTATGGCTTCCGGCAT CAGAACGCACAGGGCACCGGCCAGGCGGCCGACTATAAGTCCACACAAGCAGCCATCGATC AAATCACGGGAAAGCTCAATAGGCTGGTCGAGAAAACAAACACAGAATTCGAAAGTATCGA ATCAGAGTTCTCCGAGATAGAGCACCAGATCGGAAATGTGATCAATTGGACAAAGGACAGC ATCACTGACATATGGACGTACCAGGCAGAGCTGCTTGTCGCCATGGAGAACCAGCATACGA TTGATATGGCAGACTCTGAAATGCTGAACCTCTACGAGAGAGTACGGAAGCAACTACGTCA GAATGCAGAGGAGGATGGGAAAGGATGCTTTGAAATCTATCATGCATGTGACGATTCTTGC ATGGAGTCAATACGCAACAATACGTACGACCACAGCCAGTATCGGGAGGAAGCGCTGCTTA ACAGACTGAATATAAATCCGGTGACACTGTCATCTGGCTACAAGGACATCATCTTATGGTT TTCGTTTGGTGCGAGTTGTTTTGTCTTACTAGCCGTCGTTATGGGTTTATTCTTTTTTTGT TTGAAGAATGGGAACATGAGGTGTACAATTTGCATT 876 ATGTACAAGATCGTGGTCATAATCGCCCTTCTCGGTGCTGTTAAGGGACTAGATAAGATAT GCCTGGGCCACCATGCCGTAGCTAACGGTACAATAGTGAAGACATTAACTAATGAGCAAGA AGAGGTGACGAACGCTACTGAGACTGTTGAGAGCACAGGCATTAACCGGCTGTGTATGAAG GGCCGCAAGCACAAGGATCTGGGAAATTGCCACCCAATTGGCATGCTGATCGGAACACCAG CGTGCGATTTGCACCTAACCGGTATGTGGGATACTCTGATTGAGCGTGAAAATGCTATTGC CTACTGTTATCCCGGCGCTACAGTCAACGTGGAAGCGCTGCGCCAGAAGATCATGGAATCT GGAGGAATTAATAAGATCTCAACTGGTTTCACCTACGGTAGCTCGATTAACAGCGCAGGAA CAACTCGTGCCTGCATGAGAAATGGAGGCAATAGCTTTTATGCTGAACTGAAATGGCTCGT GTCTAAGTCAAAGGGCCAGAATTTCCCTCAAACAACTAACACCTACAGGAATACTGACACT GCGGAACATCTGATCATGTGGGGCATTCACCACCCCTCTTCAACACAGGAGAAAAACGATC TCTACGGCACTCAGTCGCTGTCCATCTCTGTGGGGAGCTCTACCTATCGTAACAATTTCGT CCCGGTTGTTGGCGCCCGGCCACAAGTGAACGGGCAGAGCGGCCGGATCGACTTCCACTGG ACCCTCGTACAGCCTGGGGACAACATCACCTTCTCACACAACGGAGGGCTAATCGCCCCCT CAAGGGTCAGCAAGTTGATAGGCAGGGGCTTGGGAATTCAGTCGGATGCCCCAATTGATAA CAACTGCGAGAGCAAATGCTTTTGGCGCGGAGGATCCATCAATACAAGGCTCCCCTTCCAA AACCTCAGCCCCAGAACCGTTGGGCAGTGTCCTAAATATGTGAACAGGAGATCTCTGATGC TGGCCACTGGAATGAGAAATGTGCCTGAGCTGATCCAGGGCCGAGGACTGTTTGGAGCGAT CGCCGGATTTCTTGAAAACGGCTGGGAAGGCATGGTGGATGGCTGGTACGGATTTAGACAT CAGAATGCCCAAGGGACCGGCCAAGCTGCAGACTACAAAAGTACCCAGGCCGCGATAGATC AGATTACGGGAAAGCTGAACCGTCTGGTGGAAAAAACTAATACGGAGTTTGAGTCCATAGA GAGTGAGTTTTCTGAAATTGAACACCAGATTGGGAACGTGATCAACTGGACCAAGGACTCA ATCACTGATATATGGACCTACCAGGCCGAGCTCCTAGTGGCAATGGAAAACCAGCACACAA TAGACATGGCCGACAGCGAAATGTTGAATCTCTACGAAAGAGTGAGGAAGCAGCTTCGGCA GAATGCTGAGGAGGACGGAAAGGGATGTTTCGAGATCTACCACGCCTGTGACGATAGTTGC ATGGAAAGCATCCGTAACAATACCTACGATCACAGTCAATATAGGGAAGAAGCATTGCTGA ATAGGTTGAATATAAATCCCGTTACTCTTTCCTCGGGGTATAAGGATATTATCCTTTGGTT TTCATTTGGTGCCTCGTGTTTCGTCCTGCTGGCAGTGGTGATGGGCCTCTTTTTCTTCTGT TTGAAGAACGGGAATATGCGCTGTACCATCTGCATA 877 ATGTACAAAGTAGTCGTAATCATCGCCCTTTTGGGAGCCGTCAAGGGCCTGGACAAGATAT GCCTGGGACATCACGCTGTCGCCAACGGGACGATTGTCAAAACACTGACAAACGAGCAGGA AGAGGTTACCAACGCGACTGAGACTGTTGAGTCAACAGGTATAAACCGACTGTGTATGAAA GGACGGAAACACAAAGATCTGGGGAATTGCCACCCCATCGGGATGCTGATCGGTACCCCTG CATGCGACCTGCACCTCACTGGTACTTGGGATACTCTCATAGAACGGGAGAACGCAATCGC ATACTGCTATCCTGGAGCCACCGTTAATGTTGAGGCCTTGAGACAAAAAATTATGGAGAGT GGGGGAATCGACAAAATCTCCACCGGCTTTACCTATGGCAGCTCCATCAATTCAGCCGGTA CCACGCGTGCCTGTATGCGCAACGGAGGTAATTCATTCTACGCCGAGCTAAAATGGCTGGT GTCCAAAAATAAAGGGCAAAACTTCCCGCAAACAACAAACACTTACAGAAACACAGACACT GCAGAACATCTGATAATGTGGGGAATCCACCATCCGTCATCTATACAGGAGAAAAACGATC TGTATGGCACTCAGTCACTCAGTATCTCCGTCGGCTCATCAACGTACAGGAATAATTTTGT GCCCGTCGTCGGCGCACGTCCACAAGTCAACGGTCAGTCCGGGAGAATCGACTTTCATTGG ACGCTTGTTCAACCGGGCGATAACATTACATTTTCACATAACGGAGGGCTCATCGCTCCAA GTAGAGTCTCTAAACTGATCGGACGTGGCCTGGGAATTCAGTCAGATGCGCCCATCGACAA CAATTGCGAGTCGAAGTGCTTCTGGCGGGGGGGGTCCATAAATACCCGCCTCCCCTTTCAA AACCTCTCACCCCGTACCGTGGGCCAGTGCCCTAAATATGTGAATCGGCGATCCCTGATGC TGGCAACTGGAATGCGCAACGTACCAGAGCTGATTCAGGGCAGAGGACTCTTCGGGGCCAT TGCAGGGTTCCTGGAAAATGGTTGGGAAGGAATGGTTGACGGATGGTATGGCTTCCGCCAC CAGAATGCACAAGGGACAGGTCAGGCTGCAGATTATAAGTCCACGCAGGCCGCTATTGATC AGATTACGGGAAAACTCAACAGACTGGTGGAAAAAACCAACACTGAGTTTGAGAGCATTGA GTCCGAGTTTTCCGAGATTGAACATCAAATCGGTAATGTTATCAATTGGACTATGGATAGT ATTACGGATATTTGGACTTACCAGGCCGAATTGTTAGTGGCTATGGAAAACCAACACACTA TTGACATGGCAGACTCAGAGATGCTCAATCTTTATGAGCGCGTGAGGAAGCAGCTCAGACA GAACGCGGAAGAAGACGGCAAGGGGTGCTTTGAGATTTACCACGCCTGCGACGACTCCTGC ATGGAAAGCATCCGCAACAACACCTACGACCACAGCCAATATCGCGAGGAGGCCCTCCTTA ATCGGTTGAACATCAATCCCGTAACACTGTCCTCCGGGTACAAAGACATCATCCTGTGGTT CAGTTTTGGCGCGAGCTGTTTCGTCTTGTTGGCTGTGGTGATGGGCCTCGTATTTTTTTGC CTTAAAAACGGGAACATGCGGTGTACAATCTGTATT 878 ATGTACAAAATAATTGTGATCATTGCCCTCCTGGGGGCTGTGAAGGGCCTTGACAAGATCT GCCTAGGACACCATGCAGTTGCAAACGGAACAATTGTGAAGACCCTAACCAACGAACAAGA GGAGGTGACAAACGCAACTGAGACCGTGGAGTCAACCGGCATAAATAGGCTTTGCATGAAG GGAAGGAAACACAAAGATCTCGGCAACTGTCATCCAATCGGCATGCTTATCGGGACGCCTG CATGTGATCTGCACCTAACTGGCACCTGGGACACACTGATTGAAAGGGAGAATGCTATCGC TTACTGTTACCCTGGTGCTACTGTGAACGTTGAGGCTTTGCGGCAGAAAATCATGGAGTCA GGGGGCATTGACAAAATCTCGACAGGCTTTACCTACGGCTCAAGCATTAACTCCGCTGGGA CCACTAGAGCATGTATGAGAAATGGAGGTAACTCATTCTATGCCGAGCTCAAATGGCTCGT GTCAAAAAGCAAGGGGCAGAACTTCCCGCAGACGACCAATACTTATCGGAATACAGACACT GCCGAACATCTTATTATGTGGGGAATTCATCATCCATCCTCAACTCAGGAAAAAAACGACT TGTACGGGACTCAATCCCTCTCCATTTCCGTGGGCAGTAGCACATATAGGAATAATTTCGT TCCTGTCGTTGGGGCGAGGCCACAAGTGAATGGCCAGAGCGGCCGAATCGATTTTCATTGG ACCCTTGTACAACCAGGGGACAATATCACTTTCTCACACAACGGAGGGTTGATTGCCCCAT CCCGCGTTAGTAAGCTTATCGGCCGCGGCCTGGGTATACAGTCCGATGCACCCATCGATAA TAATTGTGAGTCTAAGTGTTTTTGGCGAGGTGGCTCCATCAATACGCGGCTACCTTTTCAG AACCTGTCGCCTCGCACCGTAGGGCAGTGTCCAAAGTATGTCAATAGACGGTCTTTGATGT TGGCCACCGGAATGAGAAACGTTCCAGAGCTGATTCAGGGGCGCGGGCTGTTCGGCGCCAT CGCCGGCTTCCTTGAGAATGGGTGGGAGGGCATGGTTGATGGATGGTACGGGTTTCGGCAC CAGAACGCCCAGGGGACCGGCCAAGCCGCAGATTACAAGAGCACCCAGGCTGCCATCGACC AGATTACCGGCAAGCTCAATAGGCTCGTGGAAAAAACTAACACCGAGTTTGAGTCTATCGA ATCGGAGTTTAGCGAGATAGAGCATCAGATTGGAAATGTCATAAATTGGACAAAAGACAGT ATCACAGATATCTGGACATACCAGGCTGAGCTGCTGGTCGCTATGGAAAATCAGCACACTA TTGATATGGCCGATTCAGAAATGTTGAACCTGTATGAGCGGGTGCGTAAGCAGCTCCGACA GAATGCTGAGGAAGATGGGAAGGGCTGCTTCGAGATATACCACGCTTGTGATGACTCTTGC ATGGAGAGCATCCGGAACAACACGTATGACCATAGTCAGTATCGGGAAGAGGCACTGCTCA ACAGGCTGAATATCAATCCCGTGACGCTCTCATCTGGATACAAGGACATCATCCTGTGGTT CAGCTTTGGGGCATCTTGTTTCGTACTTCTGGCTGTCGTCATGGGCCTGTTTTTCTTCTGC TTAAAGAACGGAAATATGAGATGTACCATATGCATA 879 ATGTATAAAGTGGTAGTCATCATCGCGTTACTGGGGGCAGTGCGAGGCCTTGATAAAATTT GTCTGGGACATCATGCCGTCGCCAACGGCACCATCGTCAAGACACTAACTAACGAGCAGGA GGAGGTCACCAATGCCACCGAGACCGTCGAAAGTAAATCGTTGGGAAAGCTATGCATGAAG GGGAGGTCCTACAACGACCTGGGTAATTGCCATCCTATTGGGATCCTCATCGGTACCCCCG CATGTGACCTGCACCTGACAGGCACATGGGATACTCTGATTGAAAGAGAGAACGCTGTAGC GTACTGCTACCCCGGCGCAACTGTCAACGAAGAAGCGCTGAGACAGAAGATCATGGAATCC GGGGGCATTTCAAAGATCTCTACCGGTTTCACGTATGGAACCAGTATCAACAGCGCAGGCA CAACAAAGGCCTGCATGCGCAATGGCGGCAATTCCTTCTACGCCGAGCTTAAATGGCTCGT CAGTAAGAATAAAGGCCAGAATTTTCCCCAGACCACCAACACTTACCGGAACACTGACACG GCCGAGCATCTCATTATTTGGGGGATTCATCATCCAAGCTCGACTCAAGAAAAGAATGATC TGTATGGCACTCAGTCTCTGTCTATCTCAGTTGGCAGCTCCACGTACCAGAATAATTTCGT GCCTGTCGTTGGGGCTAGACCCCAAGTGAATGGACAATCAGGTAGGATAGATTTTCACTGG ACCTTATTACAGCCTGGAGATAACATAACATTCAGTCACAATGGAGGATTAATAGCTCCAT CCCGCGTGTCTAAACTGATCGGCAGAGGCTTGGGCATCCAGTCTGAAGCCCCTATTGACAA TGGTTGCGAGAGCAAATGCTTTTGGAAAGGCGGAAGCATTAACACAAAGTTGCCTTTCCAG AACCTGTCTCCCCGCACTGTGGGCCAGTGTCCCAAGTACGTCAATAAACGATCTCTGATGC TGGCTACCGGTATGCGCAATGTTCCCGAAATCATGCATGGGAGAGGGCTGTTCGGGGCTAT AGCAGGATTTATCGAAAATGGATGGGAAGGGATGGTGGATGGATGGTACGGTTTCAGACAC CAAAATGCCCAGGGGACGGGGCAGGCTGCTGATTACAAAAGTACGCAGGCCGCCATTGATC AGATTACCGGCAAGCTTAATCGGCTGATTGAAAAAACGAACACCGAGTTTGAGAGCATCGA GTCCGAGTTTAGCGAGATTGAGCATCAAATTGGCAACATCATCAACTGGACAAAAGACAGC ATCACTGATATCTGGACTTACCAAGCTGAACTGCTCGTGGCCATGGAGAATCAGCACACCA TTGACATGGCAGATTCCGAGATGCTAAACCTGTACGAACGCGTCCGCAAGCAGCTCCGGCA GAACGCAGAGGAAGATGGAAAGGGGTGCTTCGAGATTTACCACGCTTGCGATGACAGCTGT ATGGAATCCATTCGAAACAATACATACGATCACTCACAGTATCGCGAGGAGGCTCTGCTCA ACCGTTTGAATATTAATCCAGTGAAGCTATCTAGCGGCTATAAGGACATAATCCTGTGGTT CAGCTTCGGCGCCTCTTGCCTAATCTTACTCGCCGTCGTGATGGGACTGGTGTTTTTTTGT CTCAAGAACGGCAACATGAGGTGCACCATATGCATC 880 ATGTATAAGATCGTGGTCATAATCGCCCTGCTGGGCGCCGTCAAAGGGCTGGACAAAATAT GCCTCGGACACCATGCTGTCGCCAATGGGACGATTGTCAAAACGCTCACCAACGAACAGGA GGAAGTTACTAACGCCACAGAAACGGTAGAATCCACAGGGATCAATCGATTGTGTATGAAG GGTCGTAAGCACAAAGACTTGGGAAACTGTCACCCCATCGGCATGCTGATCGGCACGCCTG CCTGCGATCTACATCTGACAGGCATGTGGGACACACTAATAGAGAGGGAAAACGCAATCGC CTACTGTTACCCCGGTGCCACAGTAAACGTGGAAGCTCTGCGGCAGAAGATAATGGAGTCT GGAGGAATCAATAAAATCAGCACCGGTTTCACATATGGCTCCAGTATCAACTCCGCAGGCA CTACCAGGGCTTGCATGCGCAATGGGGGAAATTCTTTCTACGCGGAGCTAAAATGGTTAGT CTCTAAGTCCAAAGGACAGAACTTTCCACAGACAACAAACACCTACAGGAATACAGATACC GCTGAGCACCTGATCATGTGGGGTATTCATCATCCCAGTTCTACTCAGGAAAAGAACGATC TGTATGGGACACAGTCGCTGAGTATATCTGTCGGTAGTAGTACATACCGTAATAATTTCGT GCCCGTTGTAGGCGCTAGACCTCAGGTGAATGGGCAATCCGGCCGGATTGATTTCCACTGG ACTCTCGTGCAGCCTGGGGATAATATCACGTTTAGCCACAATGGAGGTCTAATCGCCCCCT CCCGGGTTTCTAAACTGATTGGCCGGGGACTGGGAATCCAATCTGACGCCCCAATAGACAA CAACTGCGAATCCAAGTGTTTCTGGCGGGGCGGCTCCATAAATACGCGACTTCCCTTCCAG AACTTAAGTCCCCGGACTGTGGGTCAGTGTCCAAAATACGTGAATCGCCGGAGTCTTATGC TCGCCACAGGCATGCGTAACGTCCCGGAACTTATACAGGGCCGGGGACTGTTTGGAGCTAT CGCAGGATTCCTGGAGAACGGATGGGAGGGAATGGTGGACGGATGGTATGGTTTCCGGCAC CAAAACGCTCAAGGAACGGGCCAGGCAGCAGATTATAAGTCAACACAGGCCGCGATCGACC AAATTACTGGCAAACTCAATAGGCTGGTCGAGAAAACCAACACTGAGTTTGAGAGCATTGA ATCCGAATTCAGCGAAATCGAACACCAGATCGGCAACGTGATAAATTGGACGAAAGATTCC ATTACCGACATTTGGACATACCAGGCCGAGTTGCTGGTCGCTATGGAAAATCAGCATACGA TTGATATGGCCGATAGTGAGATGCTTAACCTGTATGAACGCGTACGCAAACAGCTGCGCCA AAATGCTGAAGAGGACGGTAAAGGCTGCTTTGAGATTTATCACGCTTGCGACGATTCATGC ATGGAAAGTATCAGAAACAATACATATGACCACAGCCAGTACAGGGAGGAAGCGCTGCTCA ATCGACTAAACATCAATCCTGTGACCCTGTCGAGTGGCTATAAAGACATAATTCTATGGTT TTCATTCGGAGCATCTTGCTTCGTCCTGCTCGCAGTTGTGATGGGACTCTTCTTCTTTTGT CTGAAAAATGGTAATATGCGGTGTACCATCTGCATT 881 ATGTACAAGATCGTGGTGATCATTGCTCTGCTTGGAGCCGTCAAGGGCCTGGATAAGATTT GCCTGGGACATCACGCTGTCGCAAATGGCACCATCGTCAAGACTTTAACAAACGAGCAGGA AGAGGTGACTAATGCCACTGAGACAGTAGAGAGCACTGGGATAAATAGGTTGTGCATGAAG GGGAGAAAGCACAAGGACCTCGGAAACTGCCACCCAATTGGTATGCTAATCGGCACTCCAG CTTGCGACTTGCATCTGACTGGCATGTGGGATACGCTGATAGAACGTGAGAATGCCATCGC CTACTGTTATCCTGGGGCTACTGTGAACGTCGAGGCTTTAAGACAAAAGATCATGGAAAGT GGCGGCATCAACAAGATAAGTACCGGGTTTACCTATGGGAGTAGTATTAATTCAGCAGGCA CAACTCGGGCCTGCATGCGGAATGGGGGGAACAGCTTCTACGCCGAGCTAAAGTGGCTTGT GAGCAAGTCCAAAGGGCAGAATTTCCCGCAGACCACCAATACTTACCGCAACACCGATACT GCAGAACACTTAATAATGTGGGGCATCCACCATCCTAGTAGCACGCAAGAGAAGAATGACT TGTACGGTACCCAGTCGCTAAGTATCAGCGTGGGCAGTTCGACATATAGAAATAACTTTGT CCCTGTTGTGGGCGCGCGCCCTCAGGTAAATGGACAGTCTGGTCGGATCGACTTTCATTGG ACCCTGGTGCAGCCAGGGGACAACATTACCTTTTCACATAATGGCGGTCTCATCGCACCCA GTCGGGTCTCAAAGCTGATCGGGCGGGGGCTGGGCATTCAGTCAGACGCTCCCATAGATAA TAATTGCGAGTCCAAGTGTTTCTGGAGAGGGGGCTCCATCAATACTAGGCTGCCTTTTCAG AACCTCTCGCCCCGGACTGTGGGGCAGTGCCCCAAATACGTAAACCGAAGATCCCTAATGC TGGCTACTGGGATGCGGAACGTACCTGAACTGATCCAGGGACGTGGGCTATTCGGAGCCAT AGCTGGATTTCTGGAAAATGGCTGGGAGGGAATGGTTGATGGGTGGTACGGGTTTCGGCAC CAGAATGCCCAGGGCACTGGGCAGGCTGCCGACTACAAATCAACTCAGGCCGCTATTGATC AAATTACAGGTAAGCTCAACCGTCTAGTTGAGAAAACAAATACTGAGTTCGAAAGCATTGA GTCTGAGTTTTCCGAGATTGAGCATCAGATCGGCAACGTTATTAATTGGACAAAGGACAGC ATCACTGACATTTGGACATACCAGGCTGAACTTCTGGTTGCAATGGAAAATCAGCACACTA TCGACATGGCTGATTCCGAGATGCTAAATCTCTACGAACGGGTCAGAAAGCAACTGCGGCA GAATGCCGAGGAAGATGGAAAAGGCTGTTTCGAAATTTACCATGCTTGCGACGACTCCTGT ATGGAGTCGATCAGGAACAACACCTACGATCACAGTCAGTATCGTGAGGAGGCACTTTTGA ACCGTCTGAACATCAACCCCGTGACCCTTTCCTCCGGGTATAAAGATATCATCCTCTGGTT CTCCTTCGGAGCATCTTGCTTCGTTCTCCTGGCCGTAGTGATGGGCCTGTTTTTTTTCTGC CTGAAGAATGGGAACATGAGATGCACCATCTGCATT 882 ATGTATAAAATCGTTGTTATTATCGCCTTATTGGGCGCTGTGAAAGGGCTGGATAAAATCT GCTTAGGGCATCATGCCGTTGCTAATGGAACGATTGTCAAAACCCTGACAAATGAGCAGGA AGAGGTTACAAACGCTACTGAGACAGTGGAAAGCACCGGGATAAACCGGTTATGTATGAAA GGTCGGAAGCACAAAGACCTAGGAAACTGCCACCCAATCGGCATGCTGATTGGTACCCCAG CATGTGATCTGCACCTAACAGGAACCTGGGACACACTCATCGAGCGGGAAAACGCCATTGC CTATTGTTATCCTGGCGCCACGGCAAACGTGGAGGCGCTGCGCCAGAAGATTATGGAGTCC GGAGGTATCGACAAAATCTCTACCGGCTTTACGTACGGGAGTTCAATTAATTCAGCCGGAA CAACCAGGGCCTGTATGCGCAATGGGGGGAATTCATTTTATGCCGAATTGAAGTGGCTCGT CTCCAAGAGCAAAGGACAGAACTTTCCTCAGACAACGAATACTTACAGAAACACCGATACC GCTGAGCACTTAATTATGTGGGGAATCCACCATCCTAGTTCAATCCAGGAAAAAAACGATC TGTACGGGACACAGAGTCTCTCTATATCTGTTGGATCTTCCACCTATAGGAACAATTTTGT TCCCGTGGTGGGCGCCAGGCCACAGGTGAATGGCCAGTCCGGGAGAATAGATTTTCACTGG ACCCTTGTCCAGCCTGGGGATAACATTACTTTCAGCCACAACGGAGGCCTCATCGCGCCAA GTAGGGTTTCCAAATTGATAGGGAGAGGCCTGGGGATTCAGTCCGACGCCCCCATAGATAA TAATTGCGAATCAAAGTGTTTTTGGAGGGGGGGGTCCATCAACACAAGACTCCCCTTTCAG AATCTGTCACCCCGAACCGTTGGCCAGTGTCCGAAATATGTGAACCGGAGGTCCTTAATGC TGGCCACTGGAATGCGGAATGTGCCAGAGCTTATCCAAGGAAGGGGACTGTTTGGAGCAAT CGCCGGCTTCCTAGAAAATGGCTGGGAGGGTATGGTGGACGGCTGGTATGGGTTTAGACAT CAGAATGCCCAAGGAACCGGTCAGGCTGCGGACTATAAGTCCACCCAGGCCGCTATCGACC AGATCACAGGTAAGCTCAACAGGCTGGTCGAGAAAACAAATACAGAGTTCGAGTCCATAGA GTCCGAGTTCAGCGAAATAGAACACCAGATTGGAAATGTGATTAACTGGACGATGGATTCC ATCACAGACATCTGGACCTACCAGGCAGAGTTACTGGTAGCTATGGAAAATCAGCATACAA TCGACATGGCCGACTCTGAAATGCTAAATCTTTACGAGAGAGTTCGTAAACAGCTTCGCCA GAACGCCGAGGAAGATGGGAAAGGGTGCTTTGAAATATATCACGCCTGTGATGATAGCTGT ATGGAATCAATTAGAAATAACACATATGACCATTCTCAGTACAGAGAAGAGGCTCTGCTCA ATAGGCTCAATATCAATCCAGTGACCCTATCCTCAGGATACAAGGACATCATACTCTGGTT CAGTTTTGGCGCCTCTTGTTTCGTTCTGTTGGCCGTCGTCATGGGCCTCGTGTTTTTTTGT TTAAAGAACGGCAATATGCGATGCACTATTTGCATC 883 ATGTATAAGATTGTAGTGATCATTGCTCTGCTCGGGGCCGTGAAGGGCCTGGATAAGATCT GCCTGGGTCACCATGCCGTCGCAAACGGCACGATTGTGAAAACACTGACGAATGAGCAGGA GGAGGTTACTAACGCTACAGAGACGGTCGAGTCAACTGGAATTAACCGGCTTTGCATGAAA GGACGAAAACACAAAGATCTTGGGAACTGCCACCCAATTGGGATGCTGATTGGAACCCCAG CCTGTGATCTGCACTTGACAGGCATGTGGGACACTCTGATCGAGAGGGAGAACGCAATAGC CTATTGCTACCCTGGCGCAACCGTGAACGTGGAGGCCTTGCGCCAGAAGATAATGGAGTCT GGGGGTATCAACAAGATCAGTACAGGTTTCACTTACGGCAGTTCTATTAACTCTGCCGGAA CCACAAGAGCATGCATGCGTAACGGAGGCAATTCCTTCTATGCCGAACTTAAATGGCTTGT CTCCAAGTCTAAGGGGCAGAACTTCCCCCAGACAACGAACACTTACCGCAATACGGACACA GCAGAACACTTAATCATGTGGGGGATCCATCATCCCAGCAGTACACAGGAGAAAAATGACT TATACGGAACTCAGAGCTTAAGTATCTCCGTGGGCAGTAGTACTTACAGAAACAATTTCGT CCCTGTCGTAGGCGCTAGGCCTCAGGTGAATGGCCAGTCTGGACGCATCGACTTCCACTGG ACTCTGGTTCAACCAGGGGACAACATCACTTTCTCGCACAACGGAGGGTTGATCGCACCCA GTCGGGTGAGTAAACTTATCGGGAGAGGCCTCGGAATACAATCCGATGCTCCCATCGATAA TAATTGCGAGAGCAAATGTTTTTGGCGCGGAGGGAGCATTAATACACGCCTGCCTTTTCAG AACTTGTCACCACGAACCGTGGGCCAATGCCCCAAGTACGTCAACAGAAGATCATTGATGC TGGCTACTGGCATGAGGAATGTGCCTGAATTAATTCAAGGAAGAGGACTGTTCGGCGCCAT CGCAGGTTTTCTTGAGAATGGGTGGGAGGGGATGGTGGATGGTTGGTATGGCTTTCGCCAC CAGAATGCGCAGGGCACAGGGCAGGCTGCTGATTACAAGTCAACCCAGGCAGCCATCGACC AGATTACTGGCAAGCTGAATAGGCTCGTTGAAAAAACCAACACAGAGTTCGAGTCAATTGA GAGCGAGTTTTCTGAAATAGAGCATCAGATAGGCAACGTGATAAATTGGACCAAAGACAGT ATCACAGACATTTGGACTTATCAAGCAGAGTTGTTGGTAGCCATGGAGAATCAACACACGA TCGACATGGCCGATAGCGAAATGCTAAACCTGTATGAGCGCGTTCGGAAGCAGCTGCGCCA GAACGCAGAGGAGGACGGGAAGGGCTGTTTCGAAATTTATCACGCTTGTGACGACAGTTGC ATGGAATCCATCCGCAACAATACGTATGATCACTCCCAGTATAGAGAAGAGGCCCTCTTGA ATAGACTGAACATCAACCCAGTGACTCTGAGCTCAGGTTACAAGGACATTATTCTCTGGTT TTCTTTCGGAGCTTCCTGCTTTGTCCTCCTCGCTGTCGTAATGGGACTCTTTTTCTTTTGC CTGAAGAACGGGAATATGAGATGCACCATTTGCATC 884 ATGTATAAGATTGTCGTTATCATTGCACTGCTTGGTGCAGTTAAAGGGCTGGATAAGATTT GTCTAGGGCACCATGCCGTGGCCAACGGGACCATAGTGAAAACACTGACCAATGAACAGGA GGAAGTCACCAATGCTACTGAAACTGTTGAATCCACCGGCATTAACCGGCTGTGTATGAAG GGCCGCAAACACAAGGACCTGGGCAATTGTCACCCCATCGGCATGTTGATTGGCACCCCTG CATGTGACTTGCACCTCACTGGCATGTGGGACACACTGATCGAACGAGAGAATGCAATTGC CTACTGCTACCCTGGTGCCACAGTGAACGTGGAGGCTCTTCGACAAAAGATCATGGAAAGC GGGGGCATCAATAAGATTTCTACAGGGTTCACATACGGTTCATCTATTAACAGTGCAGGAA CGACCCGGGCCTGCATGCGGAACGGCGGCAATTCATTCTACGCCGAATTGAAGTGGTTGGT GTCGAAGAGTAAGGGCCAGAATTTCCCGCAGACAACAAACACATATCGCAATACGGATACG GCCGAACACTTAATCATGTGGGGAATCCATCACCCTTCTTCTACCCAAGAAAAGAACGATC TATACGGCACCCAGTCCCTGTCAATTTCAGTGGGTTCTTCGACATACAGGAACAATTTCGT CCCTGTTGTCGGCGCACGGCCCCAGGTAAATGGGCAGAGTGGGAGAATCGACTTCCACTGG ACTCTGGTGCAGCCTGGGGATAACATTACGTTCAGTCACAATGGCGGCCTCATAGCCCCAT CACGGGTGAGCAAACTAATAGGACGAGGCCTGGGAATACAGTCCGACGCCCCAATCGATAA CAACTGCGAGTCAAAATGTTTCTGGCGAGGAGGCAGCATCAATACAAGACTCCCTTTTCAG AATCTTAGTCCAAGGACAGTCGGACAGTGCCCAAAATACGTGAATAGACGCAGCTTGATGT TGGCAACGGGGATGCGCAATGTTCCTGAGCTCATACAGGGTAGAGGCCTATTTGGGGCCAT CGCAGGCTTCCTGGAAAACGGATGGGAGGGCATGGTGGACGGATGGTACGGATTTCGTCAC CAGAATGCTCAAGGCACAGGTCAGGCTGCCGACTACAAATCTACCCAGGCCGCCATCGACC AGATTACCGGAAAACTGAACAGGTTGGTGGAAAAAACGAATACAGAATTCGAGAGTATTGA GAGTGAGTTCTCCGAGATCGAGCACCAAATCGGCAATGTGATTAATTGGACAAAAGACTCC ATTACCGACATCTGGACTTACCAGGCTGAGTTGCTCGTGGCGATGGAAAACCAGCATACCA TTGATATGGCCGATAGTGAAATGCTGAATCTGTACGAACGCGTCAGAAAACAGCTACGACA GAACGCGGAGGAGGATGGGAAGGGCTGCTTCGAAATCTACCACGCTTGCGATGATTCCTGC ATGGAGTCCATTCGGAATAACACGTACGACCATAGCCAATACAGGGAGGAGGCGCTCCTAA ATAGGTTGAACATAAATCCAGTTACCCTTTCTTCCGGTTACAAGGATATTATCCTGTGGTT CTCCTTTGGCGCCTCTTGTTTCGTCCTTCTCGCCGTGGTGATGGGATTATTTTTCTTCTGC CTCAAGAATGGAAATATGCGGTGTACGATCTGTATT 885 ATGTACAAAGTGGTGGTGATAATTGCTCTCCTCGGCGCCGTGAAAGGCCTCGACAAGATAT GTCTGGGCCATCATGCAGTCGCCAACGGGACCATCGTCAAGACCCTCACCAATGAACAGGA GGAGGTTACCAACGCCACTGAAACAGTTGAGTCTACTGGAATCAATCGACTGTGTATGAAG GGGAGAAAACACAAGGACCTCGGTAACTGTCATCCTATTGGGATGCTTATTGGAACACCAG CCTGTGATTTACATCTGACGGGCACCTGGGACACCCTGATCGAAAGAGAGAACGCAATTGC ATATTGCTACCCTGGCGCTACAGTTAATGTTGAAGCTCTGAGGCAAAAAATCATGGAGTCC GGGGGAATCGACAAGATTTCAACCGGCTTCACGTACGGCAGTTCTATCAACAGCGCAGGTA CCACAAGGGCCTGTATGAGGAACGGCGGAAATAGCTTTTACGCCGAACTGAAATGGCTGGT GTCAAAGAACAAAGGACAGAACTTCCCTCAGACCACAAACACATACCGGAATACAGACACC GCAGAGCACCTTATAATGTGGGGCATCCATCATCCCTCCTCTATTCAGGAGAAGAATGATC TGTACGGTACACAGTCACTCTCCATCTCTGTAGGCAGCTCCACATATCGTAATAACTTTGT CCCAGTTGTGGGAGCCCGACCACAGGTGAACGGCCAATCAGGACGAATTGATTTTCACTGG ACCCTCGTGCAGCCTGGCGACAACATAACATTCAGCCATAATGGAGGACTCATCGCCCCGT CCCGCGTGTCTAAATTAATCGGTCGGGGGCTGGGGATCCAGTCCGATGCGCCCATAGATAA CAACTGCGAGTCTAAATGCTTCTGGCGGGGCGGGTCCATTAACACTCGACTGCCCTTCCAA AATCTCAGCCCACGCACAGTAGGCCAGTGTCCAAAATATGTCAATAGACGTTCTCTAATGC TCGCCACCGGAATGAGAAATGTGCCTGAGCTGATTCAGGGAAGGGGATTGTTTGGAGCTAT AGCCGGATTCTTGGAGAATGGTTGGGAAGGCATGGTCGACGGATGGTATGGATTCAGACAC CAGAACGCTCAAGGCACGGGCCAAGCAGCCGACTACAAATCCACCCAAGCAGCCATTGATC AGATTACAGGGAAGCTGAACAGGCTGGTGGAGAAGACAAACACAGAATTCGAAAGTATTGA GAGCGAATTTTCCGAGATCGAGCACCAGATCGGTAATGTGATCAATTGGACCATGGACAGC ATAACGGACATCTGGACCTATCAGGCCGAACTCCTGGTCGCAATGGAAAATCAGCATACTA TCGACATGGCCGATAGTGAGATGTTGAACCTGTATGAGAGGGTTCGTAAGCAGCTCCGTCA GAACGCAGAGGAGGATGGTAAAGGATGTTTTGAGATCTATCACGCATGCGATGACAGTTGC ATGGAATCTATTCGTAACAATACGTACGATCATAGCCAATACCGCGAAGAAGCATTGCTGA ACCGGCTGAATATTAACCCCGTGACATTATCCTCCGGGTACAAGGACATAATTCTGTGGTT CTCCTTCGGGGCCAGCTGCTTCGTGCTGCTCGCTGTGGTCATGGGCCTGGTCTTCTTCTGC CTGAAAAATGGCAACATGCGATGCACAATATGCATC 886 ATGTACAAAATCGTCGTGATCATAGCACTGCTGGGAGCCGTAAAGGGTCTCGATAAGATCT GCCTAGGGCACCACGCAGTAGCCAATGGAACCATAGTAAAAACACTCACGAATGAGCAGGA GGAAGTTACCAACGCCACTGAAACCGTCGAATCTACCGGGATCAACAGATTGTGCATGAAA GGGCGCAAACACAAGGATCTGGGGAACTGTCACCCAATCGGAATGCTAATTGGAACACCAG CCTGTGATCTCCATTTGACAGGAATGTGGGATACACTGATAGAGCGTGAAAACGCCATAGC GTACTGTTACCCCGGCGCCACAGTGAACGTGGAAGCGTTACGACAAAAGATAATGGAATCA GGAGGCATTAATAAGATAAGTACTGGCTTTACCTACGGGTCTTCAATCAACTCTGCCGGGA CAACTAGAGCCTGTATGAGAAACGGTGGTAATTCGTTCTACGCTGAGCTGAAGTGGCTGGT GTCCAAGAGCAAAGGGCAGAATTTCCCACAGACTACAAACACCTACAGAAACACCGATACA GCCGAACACCTCATCATGTGGGGAATTCATCACCCAAGCAGCACGCAGGAGAAGAACGATT TATATGGGACACAAAGCTTGTCAATTTCCGTGGGCAGTAGCACATACAGAAATAACTTCGT GCCAGTGGTAGGGGCGGGTCCCCAGGTGAATGGACAGTCCGGCCGCATTGATTTCCATTGG ACCCTCGTGCAGCCGGGAGACAACATCACATTCAGCCACAATGGTGGACTAATCGCCCCAT CCCGCGTCTCCAAACTGATCGGGAGAGGACTGGGTATTCAGTCTGACGCGCCCATTGATAA TAACTGCGAGTCAAAATGTTTCTGGCGAGGGGGGAGCATCAATACACGATTGCCTTTTCAG AACTTGTCCCCTCGGACTGTCGGCCAGTGCCCTAAGTATGTGAATAGGAGATCCCTGATGC TTGCCACCGGAATGAGAAACGTTCCTGAGCTGATTCAGGGTCGCGGTCTATTTGGCGCAAT CGCCGGCTTTCTCGAAAACGGCTGGGAGGGCATGGTAGATGGTTGGTACGGTTTCCGGCAT CAGAACGCCCAGGGAACTGGACAAGCCGCTGATTACAAGTCAACACAGGCAGCAATCGACC AAATTACTGGCAAACTGAACCGGCTTGTCGAGAAAACCAATACTGAATTTGAGTCAATTGA ATCCGAATTTAGTGAAATTGAACACCAGATCGGCAATGTGATTAATTGGACTAAGGACTCT ATTACCGATATTTGGACTTATCAGGCTGAGCTACTTGTGGCCATGGAGAACCAGCACACAA TCGACATGGCTGATAGTGAGATGCTGAACCTTTACGAGCGAGTCAGGAAACAGCTGAGACA GAACGCCGAGGAGGATGGAAAAGGCTGTTTCGAAATCTATCATGCTTGCGACGATTCATGC ATGGAGTCAATCAGAAATAACACCTACGACCACAGTCAGTATCGCGAGGAAGCTTTACTCA ACAGACTCAATATCAATCCTGTAACATTGTCTTCCGGCTACAAAGACATCATCCTGTGGTT CTCATTTGGAGCCAGCTGCTTTGTCTTGTTGGCTGTGGTGATGGGACTGTTCTTTTTTTGC CTCAAAAATGGCAATATGAGATGTACCATTTGTATC 887 ATGTATAAGATCGTGGTGATCATTGCTCTCCTGGGCGCAGTAAAGGGTCTTGACAAGATAT GTCTTGGACACCATGCAGTGGCAAACGGCACAATTGTTAAAACACTCACCAACGAGCAGGA GGAAGTGACCAATGCCACTGAAACAGTAGAGTCCACGGGGATCAATAGGCTCTGCATGAAA GGGAGGAAGCACAAAGATCTGGGTAATTGCCATCCAATCGGAATGCTCATAGGAACACCAG CCTGCGACCTTCATCTGACCGGTATGTGGGATACATTGATCGAACGCGAGAACGCGATAGC TTACTGCTATCCCGGCGCCACAGTGAATGTGGAGGCCCTCCGACAGAAGATTATGGAGTCG GGCGGTATTAACAAAATATCCACTGGTTTTACTTACGGATCTTCGATCAATTCCGCAGGAA CAACACGAGCCTGTATGAGGAATGGCGGGAACTCTTTCTATGCTGAGCTTAAGTGGCTCGT TTCTAAGTCTAAGGGCCAGAATTTCCCTCAGACGACTAATACCTACAGGAACACGGATACA GCAGAGCACCTGATTATGTGGGGTATCCATCATCCATCTAGCACCCAAGAGAAAAATGATC TGTATGGGACCCAGTCACTTTCCATTAGCGTGGGCTCTAGTACATACAGGAATAACTTTGT ACCTGTGGTGGGGGCTAGACCGCAAGTGAATGGCCAGAGCGGCCGGATTGACTTCCACTGG ACTTTAGTCCAGCCTGGAGATAACATTACATTTTCACACAACGGCGGGCTGATTGCGCCTA GTAGGGTGAGCAAACTTATTGGACGAGGATTAGGAATCCAGAGCGATGCCCCCATCGACAA CAACTGCGAAAGCAAATGCTTTTGGAGGGGCGGTTCAATCAACACCCGTCTCCCTTTCCAG AATCTGTCCCCCCGTACCGTGGGGCAGTGTCCAAAGTATGTTAATAGAAGGTCACTGATGC TAGCCACTGGCATGCGGAATGTGCCCGAGCTGATCCAGGGCCGTGGGCTGTTCGGTGCTAT TGCAGGATTTCTGGAAAATGGCTGGGAAGGCATGGTAGATGGTTGGTACGGTTTTCGGCAC CAGAACGCCCAGGGGACCGGACAGGCGGCCGACTACAAATCCACTCAAGCCGCTATCGATC AGATTACGGGAAAGCTAAATAGACTGGTCGAAAAAACCAACACAGAGTTCGAATCCATAGA GTCCGAGTTCTCTGAGATCGAGCACCAGATCGGGAATGTGATCAACTGGACTAAGGATAGC ATTACTGATATTTGGACCTACCAGGCAGAGCTGCTGGTCGCCATGGAAAACCAACACACAA TCGATATGGCGGATAGTGAGATGCTGAACCTGTATGAAAGAGTGAGGAAACAGCTGAGACA GAACGCAGAGGAGGACGGAAAAGGGTGCTTCGAGATTTACCACGCTTGCGATGACAGTTGC ATGGAAAGCATACGCAATAACACTTACGACCATAGTCAATACCGGGAGGAGGCTCTCCTGA ATAGGCTCAACATCAATCCTGTGACCCTGAGTTCAGGTTACAAAGATATCATCTTGTGGTT TTCATTTGGGGCGAGCTGCTTTGTGCTGCTGGCCGTCGTGATGGGCCTGTTCTTTTTTTGC CTGAAGAATGGCAATATGCGATGTACCATATGCATC 888 ATGTATAAAATAGTGGTGATCATAGCACTCTTGGGAGCCGTAAAGGGACTGGATAAGATCT GCCTGGGGCATCATGCCGTTGCCAACGGCACAATCGTGAAGACCCTTACTAATGAACAAGA AGAAGTGACCAACGCTACTGAGACCGTTGAATCCACCGGCATTAACCGCCTCTGCATGAAG GGGCGGAAGCACAAAGATCTCGGCAACTGCCACCCAATCGGGATGCTGATTGGGACCCCCG CGTGCGATTTACATCTGACAGGTATGTGGGATACATTAATTGAAAGGGAGAACGCGATTGC GTACTGCTACCCTGGGGCTACCGTGAATGTCGAAGCACTCCGACAGAAGATCATGGAATCT GGGGGGATCAACAAGATCTCGACCGGTTTTACCTATGGGAGTTCTATTAACTCTGCTGGCA CAACACGGGCATGTATGCGCAATGGGGGGAATAGTTTCTATGCTGAGCTCAAATGGCTTGT ATCCAAATCCAAAGGGCAGAATTTCCCCCAGACTACAAATACCTACAGAAACACGGATACC GCTGAGCACCTAATAATGTGGGGAATTCACCATCCTTCCTCAACCCAAGAGAAGAATGATC TTTACGGGACCCAGAGTCTCAGCATTAGCGTCGGATCGTCGACTTACCGCAACAATTTCGT CCCAGTGGTCGGAGCCAGGCCACAGGTCAACGGCCAGTCTGGCAGGATAGACTTCCACTGG ACCCTGGTTCAGCCTGGAGATAACATTACATTTAGTCATAACGGCGGCCTGATTGCTCCCA GTCGCGTGTCTAAACTAATCGGACGTGGTCTGGGCATCCAATCCGATGCGCCGATCGACAA TAACTGCGAAAGCAAGTGCTTTTGGAGGGGAGGATCCATCAATACACGACTTCCCTTCCAG AACCTATCACCAAGAACCGTAGGCCAGTGCCCGAAATACGTGAATCGACGGAGTCTGATGC TGGCCACCGGCATGAGAAATGTGCCTGAGCTGATTCAGGGACGAGGACTGTTTGGCGCAAT CGCTGGCTTCCTGGAAAACGGGTGGGAAGGAATGGTCGATGGCTGGTACGGATTTCGGCAT CAGAACGCCCAAGGCACTGGCCAAGCCGCCGACTACAAGAGTACACAGGCCGCAATCGACC AGATCACAGGTAAGTTGAATCGATTGGTGGAGAAGACCAACACTGAGTTCGAATCTATTGA GAGCGAATTCAGTGAAATCGAGCATCAGATCGGAAATGTGATAAATTGGACCAAGGACTCA ATTACCGACATCTGGACATACCAAGCAGAGCTTCTGGTTGCGATGGAAAACCAACACACAA TTGATATGGCAGATTCCGAGATGCTGAACCTCTATGAGCGCGTCAGGAAGCAATTGAGGCA GAATGCAGAGGAAGATGGAAAAGGGTGTTTCGAAATCTATCACGCCTGCGACGACAGTTGC ATGGAATCGATCCGCAACAATACTTATGACCACTCACAGTATAGAGAGGAGGCTTTGCTGA ACCGGTTAAATATCAATCCTGTCACGTTGAGTAGCGGCTACAAGGATATCATCCTATGGTT TTCCTTCGGGGCGTCTTGTTTTGTGCTGTTAGCAGTGGTGATGGGACTTTTCTTCTTCTGT CTTAAAAACGGAAACATGAGATGTACCATCTGCATA 889 ATGTATAAGATCGTGGTTATCATTGCCCTCCTGGGCGCAGTCAAAGGCTTGGACAAAATCT GTCTCGGACATCACGCCGTTGCTAACGGCACCATTGTTAAGACCCTTACCAACGAGCAGGA AGAAGTGACAAATGCAACAGAAACGGTCGAGTCCACAGGCATCAACCGGCTCTGTATGAAA GGTCGGAAGCACAAGGATCTTGGGAATTGTCACCCAATAGGTATGCTGATTGGCACTCCTG CCTGCGATCTTCATCTAACTGGGATGTGGGACACCCTTATCGAACGAGAAAATGCCATTGC ATACTGTTACCCTGGTGCTACTGTCAACGTGGAAGCCCTCAGGCAGAAAATAATGGAGTCG GGTGGGATAAATAAGATAAGCACCGGGTTCACTTACGGCAGCTCCATTAATTCCGCCGGAA CTACGCGCGCCTGTATGAGAAATGGCGGTAACTCCTTCTACGCGGAGCTGAAGTGGCTGGT CTCGAAGTCTAAAGGCCAGAACTTCCCCCAAACAACAAACACCTACAGGAACACTGACACC GCTGAACACCTCATCATGTGGGGCATTCACCACCCCTCCAGCACCCAGGAAAAAAACGACT TATACGGCACACAGAGCCTTAGTATAAGCGTGGGAAGCTCAACTTATCGCAACAATTTTGT TCCAGTGGTGGGCGCAAGACCGCAGGTGAACGGGCAAAGTGGTCGAATTGACTTTCACTGG ACACTCGTGCAACCAGGCGACAATATCACCTTTTCACATAACGGAGGACTCATTGCCCCGT CCCGCGTCAGTAAGTTAATTGGGCGGGGCCTCGGCATTCAGTCAGACGCCCCTATCGATAA CAACTGTGAATCTAAGTGCTTTTGGAGAGGAGGGTCTATAAACACGAGACTCCCCTTCCAG AACTTATCGCCTCGCACTGTGGGTCAGTGTCCTAAGTACGTTAACAGACGTTCCCTGATGC TGGCAACGGGAATGAGAAACGTTCCAGAACTGATCCAGGGGCGCGGGTTATTTGGGGCTAT CGCTGGTTTCCTGGAGAATGGCTGGGAGGGAATGGTTGACGGGTGGTATGGGTTTCGTCAC CAAAACGCCCAGGGGACGGGGCAGGCCGCAGATTACAAGTCTACTCAGGCGGCCATAGACC AGATTACAGGCAAGCTGAATAGACTGGTCGAGAAGACGAACACGGAGTTTGAGTCTATTGA GTCCGAGTTCAGCGAGATTGAACATCAGATAGGTAATGTTATCAATTGGACAAAGGATAGC ATAACCGATATTTGGACATACCAGGCAGAGTTACTGGTTGCAATGGAAAATCAACACACTA TTGACATGGCTGACTCAGAGATGCTCAACTTATACGAACGAGTGAGGAAGCAACTACGACA GAACGCCGAAGAGGACGGAAAGGGTTGCTTTGAGATCTACCACGCCTGCGACGATAGCTGC ATGGAGAGCATCAGGAATAATACTTACGATCACTCACAGTACAGGGAGGAAGCCCTCTTGA ACCGTCTGAACATAAATCCTGTCACACTTAGCTCCGGCTACAAAGATATCATCTTGTGGTT TTCATTTGGCGCGTCATGTTTTGTGCTCCTAGCTGTGGTCATGGGCTTATTCTTTTTCTGC CTGAAAAATGGCAATATGAGGTGCACAATTTGTATC 890 ATGTACAAGATAGTGGTAATTATCGCGCTGTTGGGCGCAGTGAAAGGACTGGACAAGATCT GCCTGGGTCACCACGCCGTGGCCAATGGAACGATTGTGAAAACCTTGACAAACGAACAGGA GGAAGTGACCAACGCAACGGAGACTGTGGAATCAACTGGTATCAATCGGCTATGCATGAAA GGCAGAAAACACAAAGATTTGGGCAATTGCCATCCCATCGGTATGCTCATTGGAACACCCG CTTGCGACCTCCACCTGACTGGGACGTGGGATACTTTGATCGAGAGGGAGAATGCTATTGC CTACTGTTACCCTGGCGCAACAGCTAATGTGGAGGCCCTCCGGCAGAAGATCATGGAGAGC GGTGGAATCGATAAGATTTCAACTGGCTTCACATACGGCTCCTCGATCAATTCTGCCGGCA CTACTCGGGCTTGCATGAGAAACGGAGGAAATAGTTTCTATGCTGAGCTGAAGTGGCTTGT GAGTAAATCTAAAGGCCAGAACTTTCCCCAGACAACCAACACATACCGGAATACCGACACC GCAGAACATCTGATTATGTGGGGGATACATCACCCATCTAGCATTCAGGAGAAAAACGACC TGTATGGCACTCAGTCCCTGAGCATTTCCGTAGGCTCTAGTACCTACCGGAACAATTTCGT ACCCGTCGTAGGCGCCCGCCCCCAAGTGAACGGCCAGTCCGGTCGAATTGACTTCCACTGG ACACTAGTGCAGCCTGGGGACAATATCACATTTAGTCATAACGGCGGACTGATCGCCCCAT CGAGAGTGTCTAAACTGATCGGACGCGGGCTGGGTATTCAATCAGATGCCCCCATCGACAA CAACTGCGAAAGCAAATGCTTCTGGCGCGGCGGGAGTATAAACACCCGGCTTCCATTTCAG AACCTCTCTCCTCGGACCGTCGGACAGTGCCCGAAATATGTGAACCGCAGGTCACTGATGT TGGCAACTGGAATGAGGAATGTCCCCGAATTAATACAGGGCCGGGGCTTATTCGGAGCCAT CGCAGGCTTCCTGGAGAACGGTTGGGAAGGCATGGTGGATGGATGGTATGGATTTAGACAT CAAAATGCACAGGGAACAGGCCAGGCTGCCGACTACAAATCTACCCAGGCCGCGATAGATC AAATTACAGGAAAGTTGAACAGGCTGGTGGAAAAGACTAATACCGAATTTGAATCAATCGA GTCCGAATTCTCCGAAATCGAACACCAGATCGGGAATGTCATTAACTGGACTATGGATTCT ATAACCGATATCTGGACATACCAGGCAGAACTGCTAGTAGCCATGGAAAATCAACACACGA TCGACATGGCTGACTCAGAGATGCTGAACCTCTACGAGCGGGTCAGAAAACAGCTCCGACA GAATGCAGAGGAAGACGGAAAAGGCTGTTTTGAGATTTACCACGCTTGCGACGACTCTTGT ATGGAGTCCATACGGAATAATACGTACGATCACTCACAGTATAGGGAGGAGGCCCTACTGA ATAGACTGAACATCAACCCCGTCACGCTGTCTAGTGGCTATAAAGACATCATTTTGTGGTT TTCTTTCGGAGCAAGTTGCTTCGTGCTCCTCGCCGTGGTGATGGGACTCGTGTTCTTCTGC TTGAAAAATGGGAATATGCGATGTACCATTTGCATC 891 ATGTATAAAATTGTCGTGATAATCGCTCTGCTTGGCGCTGTGAAGGGCTTAGATAAGATAT GCCTCGGACACCATGCAGTTGCCAATGGCACGATAGTGAAAACATTGACCAACGAGAAAGA AGAGGTGACCAACGCTACCGAGACTGTGGAATCCACCGGTCTGAATAGACTCTGCATGAAG GGGCGGAAGCATAAGGACTTGGGCAATTGTCACCCAATTGGGATGCTCATCGGATCGCCCG CATGTGACCTGCATCTCACTGGGACCTGGGACACATTGATTGAACGAGAGAACGCTATTGC GTACTGCTACCCGGGAGCCACTGTTAATGGTGAAGCACTTCGCCAGAAGATCATGGAGTCC GGAGGCATCGACAAGATCAGCACTGGATTCACCTATGAAAGTTCCATAAACTCCGCAGGCA CTACAAGAGCTTGCATGAGGAACGGCGGGAATTCATTCTACGCTGAGCTCAAGTGGCTGGT GAGCAAATCTAAGGGACAGAATTTTCCACAGACAACCAACACGTATCGAAACACCGATACT GCAGAGCACCTTATTATGTGGGGCATTCACCATCCATCCAGCACGCAGGAGAAAAACGATC TGTACGGTACCCAGTCTCTGTCTATCTCCGTGGGATCTTCCACCTATAGAAACAATTTCGT ACCCGTAGTGGGGGCCAGGCCGCAAGTCAATGGCCAATCTGGCCGCATCGACTTCCACTGG ACCTTGGTACAGCCTGGCGACAATATCACATTCTCACACAACGGCGGCTTGATTGCTCCGA GCCGGGTGTCTAAGTTGATCGGAAGAGGGCTCGGCATCCAGTCTGATGCCCCTATCGATAA CAACTGTGAAAGTAAGTGCTTCTGGCGGGGCGGAAGTATTAATACCAGGCTGCCATTCCAG AATCTTTCCCCCCGCACCGTCGGTCAATGTCCCAAATACGTGAACAAGCGAAGCCTGATGT TGGCCACTGGGATGCGAAATGTTCCTGAGCTGATGCAGGGACGAGGACTGTTCGGAGCCAT TGCTGGGTTCCTCGAGAACGGCTGGGAGGGCATGGTTGACGGTTGGTACGGATTCAGACAC CAAAACGCGCAGGGCACGGGTCAAGCCGCCGATTACAAATCTACACAGGCGGCGATTGACC AGATTACAGGTAAGCTGAATAGACTCGTGGAGAAAACAAACACCGAATTCGAGTCAATAGA GTCCGAGTTCTCTGAGATAGAACACCAGATCGGCAATGTAATCAACTGGACGAAAGACTCT ATTACAGACATTTGGACCTACCAGGCGGAACTCCTGGTGGCTATGGAGAACCAGCATACTA TTGATATGGCTGACTCTGAGATGCTGAATCTGTACGAGCGCGTCCGGAAGCAACTGCGTCA GAATGCAGAGGAAGACGGAAAGGGGTGCTTTGAGATTTATCACGCCTGCGATGATAGCTGT ATGGAGTCAATCCGAAACAACACTTATGATCATAGCCAGTACCGTGAGGAGGCACTACTGA ACAGGCTGAACATTAATCCCGTCACCCTGAGCAGTGGCTACAAAGACATCATCTTGTGGTT CTCTTTCGGCGCCTCATGCTTTGTCTTGCTTGCCGTAGTCATGGGTTTAGTGTTTTTTTGT CTCAAAAACGGTAATATGCGGTGTACAATTTGCATC 892 ATGTACAAAATCGTGGTAATAATCGCGCTTCTGGGCGCAGTGAAGGGCCTGGACAAAATCT GCCTGGGACATCACGCTGTGGCAAATGGGACCATCGTGAAAACCCTCACCAATGAGAAAGA GGAAGTGACCAACGCCACGGAAACAGTAGAAAGCACAGGATTAAACCGGCTTTGCATGAAA GGCCGCAAGCACAAAGACCTGGGCAATTGCCATCCCATCGGGATGCTGATCGGATCACCCG CCTGTGATCTCCATCTAACCGGCACCTGGGACACTCTGATCGAAAGGGAGAACGCGATCGC TTACTGCTACCCAGGCGCTACCGTTAATGGCGAGGCTTTGCGCCAGAAGATCATGGAGTCA GGAGGGATCGACAAGATTAGTACAGGCTTCACCTATGAGAGCTCGATCAATTCCGCAGGAA CAACCCGGGCCTGCATGAGAAACGGCGGCAATTCCTTTTACGCCGAACTTAAGTGGCTGGT GAGTAAAAGCAAGGGACAAAACTTCCCACAGACCACCAACACCTACCGTAATACCGATACC GCTGAGCATTTGATCATGTGGGGAATTCATCATCCCAGCTCCACACAGGAGAAGAATGATC TTTACGGGACACAGTCACTCAGCATTTCCGTCGGTTCGAGCACTTACCGGAATAATTTTGT CCCTGTGGTCGGCGCCCGCCCTCAGGTCAACGGGCAGAGCGGCAGGATCGACTTCCATTGG ACACTAGTTCAGCCTGGCGACAATATTACCTTTAGCCACAACGGCGGTCTGATCGCTCCTT CGCGTGTCTCAAAACTGATCGGTCGGGGGTTAGGCATTCAAAGCGATGCCCCCATTGACAA CAATTGTGAATCAAAATGTTTCTGGCGCGGTGGCTCCATTAACACCAGACTGCCTTTCCAG AATCTTAGCCCAAGAACAGTCGGCCAGTGCCCCAAGTATGTGAATAAAAGGTCTCTGATGC TGGCTACCGGCATGCGTAATGTCCCAGAGCTTATGCAAGGCAGAGGACTGTTCGGCGCAAT CGCGGGTTTTCTTGAGAACGGATGGGAGGGTATGGTTGACGGATGGTACGGTTTCCGGCAC CAGAACGCCCAGGGAACTGGCCAGGCCGCAGACTACAAGTCCACACAGGCGGCAATTGACC AGATCACTGGCAAACTTAACCGTCTAGTGGAAAAAACCAACACTGAATTCGAGAGTATCGA GAGTGAGTTCTCCGAGATTGAGCATCAGATAGGGAACGTGATCAATTGGACAAAGGACTCT ATTACAGACATTTGGACTTATCAGGCCGAGCTGCTGGTGGCCATGGAGAATCAGCACACAA TCGACATGGCCGACTCTGAGATGCTCAATCTTTATGAACGGGTGCGCAAACAGCTGCGACA GAATGCAGAGGAGGATGGGAAGGGGTGCTTCGAAATCTATCACGCATGCGACGATTCATGT ATGGAGTCCATCCGGAATAATACATACGATCATAGTCAGTATCGCGAGGAAGCCTTATTGA ACAGGCTGAACATTAATCCAGTCACTCTCAGCTCAGGGTACAAGGACATCATTTTGTGGTT CTCATTTGGAGCATCGTGCTTCGTGCTCCTTGCGGTTGTCATGGGTCTGGTCTTTTTTTGC CTGAAGAATGGAAACATGAGATGCACCATATGTATC 893 ATGTACAAGATCGTGGTTATTATCGCCCTCCTGGGTGCTGTGAAAGGACTGGATAAGATCT GTCTGGGACACCATGCTGTGGCAAACGGCACTATTGTTAAAACTCTGACTAACGAGCAAGA AGAAGTTACTAATGCTACTGAGACGGTCGAAAGTACTGGAATCAATCGGCTTTGCATGAAG GGCCGGAAGCACAAAGACCTTGGGAATTGCCATCCTATTGGGATGCTGATCGGTACCCCCG CATGTGACCTCCATCTGACTGGGATGTGGGACACGCTCATCGAGAGGGAGAATGCCATCGC TTACTGTTATCCCGGAGCCACAGTTAATGTCGAAGCCTTACGACAAAAAATCATGGAGTCA GGTGGTATCAACAAGATCAGCACCGGTTTCACATACGGCTCCTCCATCAACTCAGCAGGTA CTACACGCGCATGCATGCGGAACGGCGGAAACAGTTTCTACGCCGAGCTGAAGTGGCTTGT TAGCAAATCAAAAGGTCAGAATTTCCCTCAGACTACAAACACATACCGTAACACCGATACC GCAGAACATCTCATCATGTGGGGTATTCATCACCCAAGTTCCACACAAGAAAAGAACGATC TCTACGGGACTCAATCACTCTCCATCTCCGTCGGATCCTCTACATACCGTAACAACTTTGT TCCTGTGGTGGGCGCAAGACCTCAGGTTAATGGGCAGTCAGGTAGAATTGACTTCCATTGG ACACTGGTGCAACCTGGGGACAACATCACCTTCTCCCACAACGGCGGTCTGATCGCGCCCT CAAGGGTCTCCAAGCTGATAGGTCGGGGCCTCGGCATCCAGAGCGACGCCCCGATCGATAA CAATTGTGAAAGCAAATGCTTCTGGAGGGGGGGCTCTATCAACACACGACTGCCTTTCCAG AATCTCTCTCCCCGAACCGTGGGACAGTGTCCTAAATACGTCAACAGGAGGAGCCTGATGC TCGCCACAGGTATGCGTAATGTCCCAGAGCTGATTCAAGGCCGCGGGTTATTTGGCGCGAT AGCCGGTTTTCTGGAGAACGGCTGGGAGGGAATGGTGGATGGCTGGTATGGATTCCGGCAC CAAAATGCTCAGGGAACTGGTCAAGCAGCCGACTATAAATCCACGCAGGCCGCCATCGACC AGATTACTGGCAAATTAAATCGCCTCGTGGAGAAGACTAACACTGAGTTCGAATCCATAGA GTCAGAGTTTTCCGAGATCGAGCACCAGATCGGTAATGTGATTAATTGGACCAAAGATTCC ATCACTGATATTTGGACATACCAAGCCGAGCTCTTGGTGGCTATGGAGAACCAACATACTA TCGATATGGCCGATAGCGAAATGCTCAACCTGTACGAGAGGGTCAGGAAACAGCTTCGCCA GAACGCAGAGGAAGACGGCAAAGGATGTTTCGAGATTTACCATGCGTGCGACGATTCTTGC ATGGAGAGCATTCGGAACAACACGTATGATCACAGCCAGTACAGGGAAGAGGCACTTCTGA ACCGCCTGAACATAAATCCAGTCACATTGAGCAGCGGCTACAAAGACATTATACTCTGGTT TTCATTTGGGGCCTCTTGCTTCGTCCTGCTGGCAGTGGTGATGGGATTGTTCTTCTTTTGC CTCAAAAACGGTAATATGCGCTGCACCATTTGCATC 894 ATGTATAAAATAGTGGTCATTATTGCTCTTCTCGGTGCAGTTAAGGGTCTGGATAAGATCT GCTTGGGCCATCACGCTGTTGCCAATGGGACCATAGTGAAGACCTTGACAAACGAACAGGA AGAAGTGACAAACGCCACCGAAACCGTCGAATCCACTGGCATTAACCGGCTGTGCATGAAG GGGCGAAAACACAAAGACCTCGGTAATTGTCATCCCATAGGGATGCTGATTGGTACACCTG CCTGTGACCTGCACCTGACCGGAATGTGGGATACGCTCATTGAACGAGAGAATGCCATCGC CTATTGTTATCCGGGTGCAACTGTGAACGTGGAGGCCCTGCGTCAAAAGATCATGGAAAGC GGGGGGATAAACAAAATCTCGACCGGTTTCACGTATGGTTCAAGCATTAACAGTGCCGGCA CAACAAGGGCATGCATGCGCAATGGAGGTAACTCATTCTACGCCGAGCTCAAGTGGCTCGT GAGCAAGTCCAAAGGACAGAACTTCCCTCAGACTACCAATACCTACCGTAATACTGACACA GCGGAACATCTGATAATGTGGGGCATTCACCATCCTTCCTCGACCCAGGAAAAAAACGACC TGTACGGAACCCAGTCTCTCAGCATCTCCGTCGGGAGTAGCACTTACCGCAATAACTTTGT GCCCGTCGTGGGAGCCCGCCCCCAAGTGAATGGACAGAGCGGGAGGATTGATTTCCACTGG ACCCTCGTGCAACCGGGGGACAATATTACTTTCAGTCATAATGGAGGACTGATCGCCCCCA GTCGCGTGTCCAAACTGATCGGAAGGGGGCTCGGTATCCAATCCGATGCACCGATAGATAA CAATTGCGAGTCTAAGTGTTTCTGGCGTGGAGGCAGTATTAACACTCGGTTACCTTTTCAA AATCTTTCGCCGCGGACCGTTGGCCAGTGCCCTAAGTACGTCAATCGTAGGTCCCTCATGC TAGCCACTGGAATGCGCAACGTCCCGGAGCTCATCCAGGGGCGTGGATTGTTTGGAGCTAT TGCTGGCTTCCTGGAGAATGGCTGGGAGGGAATGGTCGATGGCTGGTACGGGTTTCGGCAT CAGAACGCACAGGGCACAGGCCAGGCCGCCGACTACAAGTCTACACAGGCCGCCATTGATC AGATCACCGGGAAGCTGAACCGGCTGGTTGAGAAGACCAATACCGAATTTGAGAGCATCGA ATCGGAATTCTCGGAAATCGAGCACCAGATTGGTAACGTAATAAACTGGACAAAGGATTCC ATTACGGACATTTGGACGTATCAAGCAGAACTGCTCGTGGCCATGGAGAACCAACACACGA TTGATATGGCAGATTCAGAAATGCTAAACTTGTACGAACGGGTCAGAAAGCAGCTGCGTCA GAATGCTGAGGAGGACGGCAAGGGATGTTTTGAGATCTACCATGCTTGCGATGATTCTTGT ATGGAGTCCATTCGGAATAACACGTACGACCATTCACAATATCGGGAGGAAGCACTTTTAA ACCGGCTGAATATCAATCCAGTCACACTGAGTTCAGGCTACAAGGATATCATATTATGGTT CTCATTCGGTGCCTCATGCTTCGTCCTTTTGGCAGTGGTGATGGGTTTGTTCTTTTTTTGT CTGAAGAATGGCAACATGAGATGTACAATATGCATC 895 ATGTACAAGATTGTGGTGATCATCGCACTCCTTGGAGCTGTGAAAGGACTGGACAAAATTT GTCTGGGACATCACGCTGTGGCTAACGGGACCATCGTGAAAACCCTAACGAATGAGCAGGA AGAAGTCACAAATGCGACAGAGACAGTGGAATCCACTGGTATCAATCGACTGTGTATGAAG GGCAGAAAACACAAGGACCTGGGCAATTGTCATCCGATAGGCATGTTAATCGGGACACCAG CCTGTGACCTGCATCTGACCGGCATGTGGGATACTCTTATTGAGCGGGAGAACGCAATAGC TTACTGCTACCCAGGCGCTACTGTGAATGTGGAAGCTCTGCGTCAGAAAATTATGGAGAGC GGAGGGATTAACAAAATCTCTACTGGTTTCACATACGGCAGCAGTATTAACTCAGCCGGCA CCACCAGGGCGTGTATGCGGAATGGTGGAAACTCATTTTATGCTGAGCTTAAATGGCTTGT CTCAAAGTCGAAAGGCCAGAACTTCCCCCAGACTACAAACACCTACAGGAATACGGATACA GCCGAGCATCTCATTATGTGGGGAATACATCATCCCAGCAGTACCCAGGAGAAAAACGATC TGTACGGAACCCAGAGTCTCTCAATCTCAGTGGGATCAAGCACGTACAGAAATAATTTCGT CCCTGTGGTGGGAGCCAGACCCCAGGTAAATGGACAGTCAGGGCGCATTGACTTTCACTGG ACTCTCGTCCAGCCAGGAGACAATATCACATTTAGTCACAATGGCGGCCTGATAGCTCCTT CTCGAGTGAGCAAACTGATCGGACGGGGTCTCGGTATCCAGTCCGACGCCCCCATCGATAA CAACTGCGAGTCGAAGTGCTTCTGGCGTGGCGGGTCAATTAACACAAGACTACCATTTCAG AACCTTTCACCTAGAACCGTGGGACAGTGCCCAAAGTACGTCAATAGACGGAGCCTGATGC TGGCCACAGGGATGAGGAACGTTCCTGAACTGATACAAGGTCGGGGGCTTTTCGGTGCCAT CGCAGGTTTTCTCGAGAACGGCTGGGAGGGCATGGTGGATGGGTGGTATGGGTTTAGGCAC CAAAATGCACAAGGGACCGGCCAGGCCGCCGATTATAAGTCTACGCAAGCCGCCATTGACC AGATCACTGGGAAGCTTAATAGGTTAGTAGAGAAGACAAATACCGAATTCGAGAGTATTGA GTCAGAATTCTCCGAGATCGAGCACCAGATAGGCAACGTCATTAATTGGACAAAGGACTCT ATTACCGACATTTGGACGTATCAAGCCGAACTTCTGGTGGCAATGGAAAATCAGCACACAA TCGACATGGCCGACTCGGAGATGTTGAACTTATATGAAAGGGTGCGCAAACAGCTGCGCCA GAACGCTGAAGAAGACGGTAAGGGATGCTTTGAGATCTATCATGCCTGCGATGATTCCTGT ATGGAGTCGATAAGAAACAATACCTATGACCATAGCCAGTACCGGGAAGAAGCCCTCCTGA ACAGACTGAATATTAACCCCGTTACCTTGTCCTCAGGATACAAGGACATTATCCTGTGGTT TTCTTTCGGTGCTAGCTGTTTCGTGCTGCTCGCCGTCGTAATGGGGTTGTTTTTCTTCTGC CTCAAAAACGGTAACATGCGATGCACCATTTGCATT 896 ATGTATAAGATCGTCGTCATTATCGCTCTCCTCGGAGCCGTGAAAGGTCTTGACAAAATTT GTCTGGGCCATCACGCAGTGGCCAATGGGACCATCGTGAAGACGCTGACGAACGAGAAAGA AGAGGTGACAAACGCTACTGAGACGGTCGAGAGCACCGGACTCAATAGGTTGTGCATGAAA GGACGAAAGCATAAAGATCTGGGCAACTGTCACCCCATCGGGATGCTGATTGGCTCCCCAG CCTGCGACTTACACCTGACTGGCACCTGGGATACACTGATCGAGCGCGAGAACGCCATTGC CTACTGTTACCCCGGCGCTACAGTGAATGGTGAGGCCCTTCGCCAAAAGATTATGGAGTCA GGCGGAATAGATAAGATCTCTACAGGCTTCACTTATGAGAGTTCGATTAACTCGGCCGGGA CAACTAGGGCGTGTATGCGGAATGGCGGGAATTCCTTCTATGCTGAGCTTAAGTGGTTGGT TTCCAAGAGCAAGGGGCAGAATTTTCCTCAGACCACCAACACCTATCGAAACACAGACACC GCTGAACACCTCATCATGTGGGGCATTCACCACCCATCTTCAACCCAGGAGAAGAACGACC TCTACGGTACTCAAAGCCTTAGTATCAGCGTGGGGTCATCTACCTACCGGAACAATTTTGT GCCCGTGGTGGGAGCGCGCCCTCAAGTGAACGGACAAAGTGGCAGGATCGATTTCCATTGG ACTTTGGTCCAGCCTGGTGACAACATCACATTCAGTCACAACGGTGGCCTGATCGCACCGT CCAGAGTTTCCAAACTGATCGGCCGGGGTCTAGGGATTCAGAGCGACGCCCCTATTGATAA CAACTGCGAGTCAAAATGCTTCTGGAGGGGGGGCTCCATTAACACTCGACTGCCCTTTCAG AATCTGTCACCCCGAACCGTGGGTCAGTGTCCTAAGTACGTGAACAAGAGATCACTCATGC TTGCCACTGGGATGCGCAATGTGCCCGAGCTCATGCAGGGAAGAGGACTGTTCGGAGCGAT TGCTGGGTTTCTGGAAAATGGGTGGGAAGGGATGGTAGATGGATGGTACGGATTTCGTCAT CAAAACGCACAGGGCACTGGACAAGCGGCGGACTATAAGTCAACTCAGGCTGCCATAGACC AAATAACCGGGAAACTAAACCGGCTCGTCGAGAAGACCAACACCGAATTTGAATCTATCGA GTCGGAATTTAGCGAGATTGAGCACCAGATAGGAAATGTTATCAATTGGACCAAGGACTCC ATTACGGATATTTGGACTTACCAGGCGGAGCTGCTGGTTGCCATGGAGAATCAGCACACTA TTGACATGGCCGATAGTGAGATGTTGAATTTGTACGAAAGAGTGCGCAAGCAGCTGAGGCA GAACGCTGAAGAGGACGGTAAGGGATGCTTCGAAATTTATCACGCATGCGATGATTCCTGC ATGGAATCGATCAGAAACAATACATATGATCATTCTCAATACCGGGAGGAGGCTTTGCTCA ACCGCCTGAATATAAATCCTGTGACTCTCAGTTCGGGCTATAAAGACATCATCCTGTGGTT CTCTTTTGGCGCCTCCTGCTTTGTCCTGCTGGCGGTGGTGATGGGACTCGTCTTCTTCTGC CTAAAGAATGGCAACATGCGGTGTACAATCTGTATT

An alignment of amino acid sequences of hemagglutinin proteins from influenza A H7N9 strains are shown relative to a consensus sequence in FIG. 22. An alignment of amino acid sequences of hemagglutinin proteins from influenza A H10N8 strains are shown relative to a consensus sequence in FIG. 23.

Aspects of the present disclosure provide RNA polynucleotides encoding an influenza hemagglutinin protein or a fragment thereof. The terms “hemagglutinin,” “hemagglutinin protein,” and “HA” may be used interchangeably throughout and refer to a hemagglutinin protein that may be present on the surface of an influenza virus. On the viral surface, the hemagglutinin protein is present in homotrimers, each monomer of which is comprised of two subunits, HAI and HA2, linked by a disulfide bond. Structurally, hemagglutinin proteins are comprised of several domains: a globular head domain, a stalk domain (also referred to as a stem domain), a transmembrane domain, and a cytoplasmic domain. It is generally though that during infection of a host cell (e.g., a eukaryotic cell such as a human cell) with an influenza virus, the hemagglutinin protein recognizes and binds to sialic acid of a receptor on the surface of a host cell facilitating attachment of the virus to the host cell (Gamblin et al., 2004; Ha et al., 2000). Following endocytosis of the virus and acidification of the endosome, the hemagglutinin protein undergoes a pH-dependent conformational change that allows for the hemagglutinin protein to facilitate fusion of the viral envelope with the endosome membrane of host cell and entry of the viral nucleic acid into the host cell.

In general, influenza viruses are classified based on the amino acid sequence of the viral hemagglutinin protein and/or the amino acid sequence of the viral neuraminidase (NA). In some embodiments, the hemagglutinin is of the subtype H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, or H18. The differences in amino acid sequences between hemagglutinin proteins of different subtypes are largely found within the sequence of the head domain of the protein. The amino acid sequence of the stalk domain is considered to be more conserved between hemagglutinin subtypes compared to sequence of the head domain. Domains of the hemagglutinin protein may be predicted using conventional methods known in the art.

Many naturally occurring and experimentally derived antibodies that bind and neutralize the hemagglutinin protein are thought to bind epitopes within the head domain of hemagglutinin and prevent or reduce interaction of hemagglutinin with sialic acid on receptors of host cells, thereby preventing or reducing infection of the cell. Alternatively or in addition, neutralizing antibodies may prevent or reduce fusion of the virus membrane with the membrane of the endosome. Such antibodies may bind epitopes within the stalk domain, thereby inhibiting the conformations change of the protein.

In some embodiments, the RNA polynucleotides described herein encode a fragment of a hemagglutinin protein, such as a truncated hemagglutinin protein. In some embodiments, the fragment is a headless hemagglutinin, meaning the fragment does not comprise the head domain In some embodiments, the fragment comprises a portion of the head domain. In some embodiments, the fragment is a stalk fragment (see, e.g., Mallajosyula et al. PNAS (2014) E2514-E2523). In some embodiments, fragment does not comprise the cytoplasmic domain. In some embodiments, the fragment does not comprise the transmembrane domain. In such embodiments, the fragment may be referred to as a soluble or secreted hemagglutinin protein or fragment.

In some embodiments, the RNA polypeptide encodes a hemagglutinin protein or fragment thereof that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to a hemagglutinin protein provided by an amino acid sequence in Table 14-16. The terms “identical” or percent “identity” in the context of two or more polypeptide sequences refer to two or more sequences that are the same. The percent identity between polypeptide sequences may be performed using algorithms known in the art, such as BLAST and CLUSTAL.

The sequence of the hemagglutinin protein or fragment thereof may be obtained from any source. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from an avian influenza strain. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from an avian influenza strain that is capable of or at risk of infecting human subjects. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from a porcine influenza strain. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from a porcine influenza strain that is capable of or at risk of infecting human subjects.

In any of the embodiments described herein, the sequence of the hemagglutinin or fragment thereof may be modified or optimized (such as codon optimized) for expression in a particular cell or host organism.

Methicillin-Resistant Staphylococcus Aureus (MRSA)

MRSA is the most common invasive bacterial infection with an incidence of 20-100 per 100,000 persons. It is responsible for ˜20,000 deaths in U.S. alone

Risk factors for MRSA include healthcare exposure, antibiotic use, and HIV. It is a common complication of joint replacement surgery which then requires removal and replacement of the joint. Symptoms include pneumonia, skin and soft-tissue infections, osteomyelitis (e.g., prostheses), endocarditis, bacteremia and sepsis.

Current treatment includes intravenous anti-staphylococal antibiotics (e.g., Vancomycin, Zyvox, Cubicin), contact precautions, and managment of sepsis (Goal-directed therapy +/−ICU admission).

The MRSA HA pathogens have multiple antigens so a combinatorial approach is an important principle to combat multi-drug resistance. Cell culture limits number of antigens in traditionally-produced vaccines making the present NAV approach superior.

MRSA antigens may include but not limited to NDM1, mecA, all b-lactamases (antibiotic resistance); Protein A mutant (immune escape); SDRD/SDRE (adherence); IsdA or IsdB (Lactoferrin excape, Fe transport); TSST, a-HL, and PVL(toxins).

In one embodiment, the NAVs of the present invention may comprise a multivalent vaccine, e.g., comprising a polynucleotide which encodes at least two MRSA antigens, including but not limited to NDM-1 and SpAmut.

In one embodiment, the SpA antigen or loss of function mutant SpAKKAA of MRSA is encoded by a polynucleotide of a NAV. Kim et al. (J. Exp. Med. Vol. 207 No. 9; 1863-1870; the contents of which are herein incorporated by reference in its entirety) describes that the mutation of the staphylococcal protein A (SpA) at five Ig-binding domains resulted in variant SpAKKAA which cannot bind to Fcγ or Fab V_(H)3 and promote cell apoptosis. Immunization of mice with SpAKKAA raised antibodies was found to protect mice against challenge with highly virulent MRSA strains and even enabled MRSA-challenged mice to mount antibody responses to different staphylococcal antigens. Falugi et al. (mBio 4(5):e00575-13. doi:10.1128/mBio.00575-13; the contents of which are herein incorporated by reference in its entirety) found that the SpAKKAA mutant elicited B cell responses to key virulence antigens that protected animals against a lethal S. aureus challenge and the SpAKKAA mutant was able to elicit an adaptive response that protected against recurrent infection. Schineewind et al. describes a SpA antigen or loss of function mutant of SpA in International Patent Publication Nos. WO2011127032, WO2011005341, WO2012003474, WO2012034067 and WO2013025834 and US Patent Publication Nos. US20130136746, US20120114686, US20130171183 and US20130230550, the contents of each of which are herein incorporated by reference in their entirety. As a non-limiting example, the SpA mutant may comprise at least one substitution in the amino acid sequence that disrupts the Fc binding and at least one substitution in the amino acid sequence that disrupts the VH3 binding (see e.g., International Publication No. WO2011005341 and US Patent publication No. US20120114686, the contents of each of which are herein incorporated by reference in its entirety). As another non-limiting example, the SpA mutant may comprise a substitution in the D domain of a SpA sequence at positions 9, 10, 36 and 37 of the SpA sequence (see e.g., International Patent Publication Nos. WO2011127032, WO2012003474 and WO2012034067 and US Patent Publication Nos. US20130136746, US20130171183 and US20130230550, the contents of each of which are herein incorporated by reference in their entirety). The amino acids at positions 9 and 10 may be substituted for glycine and the amino acids at positions 36 and 37 may be substituted for serine (see e.g., International Patent Publication Nos. WO2011127032 and WO2012003474 and US Patent Publication Nos. US20130136746 and US20130171183, the contents of each of which are herein incorporated by reference in their entirety). As yet another non-limiting example, the SpA mutant may comprise a substitution at position 9, 10, 36 and 37 of SEQ ID NO: 2 described in International Patent Publication Nos. WO2011127032 and WO2012003474 and US Patent Publication Nos. US20130136746 and US20130171183, the contents of each of which are herein incorporated by reference in their entirety.

SpA-binding to B-cell surface V(H)3 leads to B-cell receptor crosslinking followed by B-cell apoptosis, clonal B-cell deletion and block of affinity maturation and B-cell memory. SpA-binding to Fcg at the FcR-binding site of secreted antibodies inhibits activation of effector cells critical for bacterial clearance and adaptive immunity.

SpAKKAA is a loss-of-function mutant of SpA without a functional Fcg and V(H)3 binding site.

Vaccination with SpAKKAA allows clonal B-cell expansion and sufficient time for antibody affinity maturation leading to B-cell clones with higher affinity to SpA epitopes than Fcg or V(H)3 binding of SpA. This enables antibody binding to SpA through affinity-matured CDRs with Fc portions freely available for effector cell activation and B-cell memory creation.

Thus, SpAKKAA immunization enable MRSA-challenged subjects to mount antibody responses to many different staphylococcal antigens.

In one embodiment, the NAV is a multi-valent vaccine with SpAKKAA as the center antigen. This provides a key advantage over inactivated, whole MRSA vaccines currently in clinical development.

In one embodiment, the MRSA NAVs are used to target at risk populations such as those having linezolid-resistant joint/bone infections; chronic disease; healthcare workers and to prevent outbreak of resistant strains.

MRSA toxins such as PVL, a-HL, TSST-1 may be encoded by the NAVs of the invention. Alternatively, any of the beta-lactamase genes may be targeted in a manner which reduces their ability to protect the bacteria thereby rendering it more susceptible to traditional antibiotic attack. Such targeting of the lactamase enzymes may be personalized to a particular subject where a sample is obtained and the unique lactamase sequence is determined through standard techniques in the art. Inhibitors of the unique lactamase sequence can then be designed creating a personalized medicine or vaccine.

Dengue

Dengue fever is a mosquito-borne virus and is epidemic (SE Asia) and endemic (Sub-Saharan Africa, India). As much as 40% of world's population is at risk with over 100 million infections per year according to the World Health Organiztion. There have been about 1-2 million clinically documented cases. The mortality rate depends on access to healthcare and can reach as high as 20%.

Symptoms include acute onset fevers with terrible joint and muscle pain for 5-7 days, followed by weeks of lethargy and fatigue. Dehydration and hemorrhage are the main drivers of mortality, hence need for access to IV fluids to avoid shock.

Supportive care includes fluid resuscitation but prevention is the primary means of limiting the impact of virus (e.g., mosquito control, personal protection).

For Dengue fever, disease characteristics requires a neutralizing—but not enhancing—antibody response to the four most critical Dengue serotypes (DENV1-4). Therefore a multivalent antigen targeting key proteins/protein domains of four serotypes of Dengue virus (DENV 1-4) would have value as a vaccine.

In one embodiment, NAVs of the invention comprise one or more polynucleotides which encode the E protein domain III (DENV1-4 tandem mRNA), the E protein domain I/II hinge region (DENV1-4 individual mRNAs), the prM protein (DENV1-4 tandem or individual mRNAs) and the C protein (DENV1-4 tandem or single mRNAs).

In one embodiment, the most potent NAV vaccine is selected by measuring the antibody titer in Balb/c mice followed by tests of selected vaccines in Dengue disease models. Upon rescue in disease model, crossreactivity analysis in in-vitro viral assays to ensure activity of multi-valent vaccine against all serotypes is performed.

In some embodiments cross-neutralizing Ab-titers agains each of the four Dengue strains (DENV1-4) in a virus neutralization assay are tested either in vitro or in vivo as in (BMC Microbiol. 2014; 14: 44; and Immunology. 2012 July; 136 (3):334-43), the contents of which are incorporated herein by reference.

In some embodiments, neutralizing vs enhancing Ab-titers is evaluated and in another embodiment the RNAVare tested in humanized mouse model for Dengue disease (J Virol. 2014 February; 88(4):2205-18, thencontents of which are incorporated herein by reference in their entirety).

The NAV targeting Dengue is referred to as a multi-genotype antigen NAV.

Enterotoxic E. Coli (ETEC)

ETEC is the most common cause of diarrhea in the developing world with between 300k-500k deaths per year. Transmission is via fecal-oral transmission (water, food). Sympoms include secretory diarrhea (mediated by two toxins: heat-stable and heat-labile), abdominal pain and cramping, nausea and vomiting. Generally symptoms last less than 1 week, and rarely greater than 2 weeks. The resultant dehydration is the primary cause of more serious sequelae. Currently supportive care and fluid resuscitation are the treatment where generally an uncomplicated infection resolves on its own.

Previous ETEC vaccines were based on a single antigen or had a sole focus on toxin neutralization that was not effective in providing long-lasting immunity.

According to the present invention three pathways are addressed by the selected antigens in a multivalent approach: (1) Toxins: Sta3 and eltA/eltB; (2) Adhesion proteins critical for delivery of toxins to the endothelium: EatA, etpA, and etpB; and (3) Proteins enabling colonialization: cssA.

The ETEC NAV of the present invention is designed to enable long-term protection against ETEC. And even to provide prophylactic treatement such as for travelers.

Clostridium Difficile

C. difficile causes an increasingly common diarrheal illness associated with key risk factors including exposure to a healthcare setting (e.g., hospitalization, nursing home residence), and antibiotics (esp. amoxicillin, clindamycin).

Symptoms include recurrent diarrhea and Pseduomembranous colitis. Current treatment includes diagnostics with toxin and reflex antigen and/or treatment with metronidazole and vanocmycin.

The present invention provides a trivalent antigen approach to the treatment of C. difficile infection. The antigens encoded include toxin A (enterotoxin; CD Toxin A 136754); toxin b (cytotoxin; CD Toxin B 136755), and binary toxin (cdtB; CD cdtB 136757).

In some embodiments, the multivalent NAV prevents C. Difficile infection among patients: (1) receiving certain medications (antibiotics, PPIs) or (2) with healthcare exposure (hospitalized, nursing home etc) in a manner which blocks the effects of the organisms' toxin and key virulence factors.

Tuberculosis

Tuberculosis is an infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Symptoms include a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss.

The current challenges for the development of a vaccine against TB are (i) three different disease states requiring a different set of antigens: pre-infection (prophylactic vaccine), latent infection (therapeutic vaccine) and active infection (therapeutic vaccine); and (ii) different set of adjuvants critical to induce a protective while not overshooting immune response; and (iii) an unclear understanding on the necessary immune response to clear the infection.

Therefore it will be required to combine different sets of cytokines as an adjuvant with a different set of antigens dependent on the disease state. The following cytokines provide a potential adjuvant arm of the vaccine: GM-CSF, IL-17, IFNg, IL-15, IL-2, IL-21, Anti-PD1/2, lactoferrin. The following antigens represent a non-exhaustive list: Ag85A (Rv3804c), Ag85B (Rv1886c), TB10.4 (Rv0288), ESAT6(Rv3785), Rv2660L, Rv3619, Rv1813c, Rv3620c, Rv2608, Rv1196, Rv0125, and MT401.

Middle-East Respiratory Syndrome Coronavirus (MERS-CoV)

MERS-CoV, previously known as the Novel Coronavirus or SARS-like virus, is a member of the coronavirus family. Symptoms are similar to SARS infections and include coughing, production of mucous, shortness of breath, malaise—a general feeling of being unwell, chest pain, fever, diarrhea (in some cases) and renal (kidney) failure. Human enterovirus 71 and Human enterovirus 68

Enterovirus 71 (EV-71) is one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases. The Enterovirus 71 (EV71) infection may be asymptomatic.

Enterovirus 68 (EV68, EV-D68) is a member of the Picornaviridae family, an enterovirus (a group of ssRNA viruses containing the polioviruses, coxsackieviruses, and echoviruses). First isolated in 1962, it has been been on a worldwide upswing in the last few years. It may be involved in cases of a recent outbreak of polio-like disease in Calif.

Antigens

Antigens of the present invention include polypeptides, peptides and/or polypeptides of interest and are encoded by the polynucleotides of the invention. Polynucleotides encoding such antigens of the invention are described in more detail below under “Design, Synthesis and Quantitation of NAV Polynucleotides”.

III. Design, Synthesis and Quantification of NAV Polynucleotides

According to the present invention, the polynucleotides encode at least one polypeptide of interest, e.g., an antigen. Antigens of the present invention may be wild type (i.e., derived from the infectious agent) or modified (e.g., engineered, designed or artificial). They may have any combination of the features described herein.

The present invention provides nucleic acid molecules, specifically polynucleotides which, in some embodiments, encode one or more peptides or polypeptides of interest. Such peptides or polypeptides, according to the invention may serve as an antigen or antigenic molecule. The term “nucleic acid,” in its broadest sense, includes any compound and/or substance that comprise a polymer of nucleotides. These polymers are often referred to as polynucleotides.

Exemplary nucleic acids or polynucleotides of the invention include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a β-D-ribo configuration, α-LNA having an α-L-ribo configuration (a diastereomer of LNA), 2′-amino-LNA having a 2′-amino functionalization, and 2′-amino-α-LNA having a 2′-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) or hybrids or combinations thereof.

In one embodiment, linear polynucleotides encoding one or more antigens of the NAVs of the present invention which are made using only in vitro transcription (IVT) enzymatic synthesis methods are referred to as “IVT polynucleotides.”

In another embodiment, the polynucleotides of the present invention which have portions or regions which differ in size and/or chemical modification pattern, chemical modification position, chemical modification percent or chemical modification population and combinations of the foregoing are known as “chimeric polynucleotides.” A “chimera” according to the present invention is an entity having two or more incongruous or heterogeneous parts or regions. As used herein a “part” or “region” of a polynucleotide is defined as any portion of the polynucleotide which is less than the entire length of the polynucleotide.

In yet another embodiment, the polynucleotides of the present invention that are circular are known as “circular polynucleotides” or “circP.” As used herein, “circular polynucleotides” or “circP” means a single stranded circular polynucleotide which acts substantially like, and has the properties of, an RNA. The term “circular” is also meant to encompass any secondary or tertiary configuration of the circP.

In some embodiments, the polynucleotide includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 7,000, from 1,000 to 10,000, from 1,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, from 1,000 to 100,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 1,500 to 25,000, from 1,500 to 50,000, from 1,500 to 70,000, from 1,500 to 100,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 2,000 to 25,000, from 2,000 to 50,000, from 2,000 to 70,000, and from 2,000 to 100,000).

In one embodiment, the polynucleotides of the present invention may encode at least one peptide or polypeptide of interest. In another embodiment, the polynucleotides of the present invention may be non-coding.

In one embodiment, the length of a region encoding at least one peptide polypeptide of interest of the polynucleotides present invention is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides). As used herein, such a region may be referred to as a “coding region” or “region encoding.”

In one embodiment, the polynucleotides of the present invention is or functions as a messenger RNA (mRNA). As used herein, the term “messenger RNA” (mRNA) refers to any polynucleotide which encodes at least one peptide or polypeptide of interest and which is capable of being translated to produce the encoded peptide polypeptide of interest in vitro, in vivo, in situ or ex vivo.

In one embodiment, the polynucleotides of the present invention may be structurally modified or chemically modified. As used herein, a “structural” modification is one in which two or more linked nucleosides are inserted, deleted, duplicated, inverted or randomized in a polynucleotide without significant chemical modification to the nucleotides themselves. Because chemical bonds will necessarily be broken and reformed to effect a structural modification, structural modifications are of a chemical nature and hence are chemical modifications. However, structural modifications will result in a different sequence of nucleotides. For example, the polynucleotide “ATCG” may be chemically modified to “AT-5meC-G”. The same polynucleotide may be structurally modified from “ATCG” to “ATCCCG”. Here, the dinucleotide “CC” has been inserted, resulting in a structural modification to the polynucleotide.

In one embodiment, the polynucleotides of the present invention, such as IVT polynucleotides or circular polynculeotides, may have a uniform chemical modification of all or any of the same nucleoside type or a population of modifications produced by mere downward titration of the same starting modification in all or any of the same nucleoside type, or a measured percent of a chemical modification of all any of the same nucleoside type but with random incorporation, such as where all uridines are replaced by a uridine analog, e.g., pseudouridine. In another embodiment, the polynucleotides may have a uniform chemical modification of two, three, or four of the same nucleoside type throughout the entire polynucleotide (such as all uridines and all cytosines, etc. are modified in the same way).

When the polynucleotides of the present invention are chemically and/or structurally modified the polynucleotides may be referred to as “modified polynucleotides.”

In one embodiment, the polynucleotides of the present invention may include a sequence encoding a self-cleaving peptide. The self-cleaving peptide may be, but is not limited to, a 2A peptide. As a non-limiting example, the 2A peptide may have the protein sequence: GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 963), fragments or variants thereof. In one embodiment, the 2A peptide cleaves between the last glycine and last proline. As another non-limiting example, the polynucleotides of the present invention may include a polynucleotide sequence encoding the 2A peptide having the protein sequence GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 963) fragments or variants thereof.

One such polynucleotide sequence encoding the 2A peptide is GGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGA GGAGAACCCTGGACCT (SEQ ID NO: 964). The polynucleotide sequence of the 2A peptide may be modified or codon optimized by the methods described herein and/or are known in the art.

In one embodiment, this sequence may be used to separate the coding region of two or more polypeptides of interest. As a non-limiting example, the sequence encoding the 2A peptide may be between a first coding region A and a second coding region B (A-2Apep-B). The presence of the 2A peptide would result in the cleavage of one long protein into protein A, protein B and the 2A peptide. Protein A and protein B may be the same or different peptides or polypeptides of interest. In another embodiment, the 2A peptide may be used in the polynucleotides of the present invention to produce two, three, four, five, six, seven, eight, nine, ten or more proteins.

Polynucleotide Architecture

Traditionally, the basic components of an mRNA molecule include at least a coding region, a 5′UTR, a 3′UTR, a 5′ cap and a poly-A tail. The IVT polynucleotides of the present invention may function as mRNA but are distinguished from wild-type mRNA in their functional and/or structural design features which serve to overcome existing problems of effective polypeptide production using nucleic-acid based therapeutics. It is to be understood that the antigens of the NAVs of the present invention may be encoded by IVT polynucleotides, as described herein.

FIG. 1 shows a primary construct 100 of an IVT polynucleotide of the present invention. Such polynucleotides are useful in NAV compositions, RNAV compositions or mRNA vaccines. As used herein, “primary construct” refers to a polynucleotide of the present invention which encodes one or more polypeptides of interest and which retains sufficient structural and/or chemical features to allow the polypeptide of interest encoded therein to be translated.

According to FIGS. 1A and 1B, the polynucleotide 100 here contains a first region of linked nucleotides 102 that is flanked by a first flanking region 104 and a second flaking region 106. The polypeptide of interest may comprise at its 5′ terminus one or more signal sequences encoded by a signal sequence region 103. The flanking region 104 may comprise a region of linked nucleotides comprising one or more complete or incomplete 5′ UTRs sequences which may be completely codon optimized or partially codon optimized. The flanking region 104 may include at least one nucleic acid sequence including, but not limited to, miR sequences, TERZAK™ sequences and translation control sequences. The flanking region 104 may also comprise a 5′ terminal cap 108. The 5′ terminal capping region 108 may include a naturally occurring cap, a synthetic cap or an optimized cap. Non-limiting examples of optimized caps include the caps taught by Rhoads in U.S. Pat. No. 7,074,596 and International Patent Publication No. WO2008157668, WO2009149253 and WO2013103659, the contents of each of which are herein incorporated by reference in its entirety. The second flanking region 106 may comprise a region of linked nucleotides comprising one or more complete or incomplete 3′ UTRs. The second flanking region 106 may be completely codon optimized or partially codon optimized. The flanking region 106 may include at least one nucleic acid sequence including, but not limited to, miR sequences and translation control sequences. The flanking region 106 may also comprise a 3′ tailing sequence 110. The 3′ tailing sequence 110 may include a synthetic tailing region 112 and/or a chain terminating nucleoside 114.

Non-liming examples of a synthetic tailing region include a polyA sequence, a polyC sequence, and/or a polyA-G quartet. Non-limiting examples of chain terminating nucleosides include 2′-O methyl, F and locked nucleic acids (LNA).

Bridging the 5′ terminus of the first region 102 and the first flanking region 104 is a first operational region 105. Traditionally this operational region comprises a Start codon. The operational region may alternatively comprise any translation initiation sequence or signal including a Start codon.

Bridging the 3′ terminus of the first region 102 and the second flanking region 106 is a second operational region 107. Traditionally this operational region comprises a Stop codon. The operational region may alternatively comprise any translation initiation sequence or signal including a Stop codon. Multiple serial stop codons may also be used in the IVT polynucleotide. In one embodiment, the operation region of the present invention may comprise two stop codons. The first stop codon may be “TGA” or “UGA” and the second stop codon may be selected from the group consisting of “TAA,” “TGA,” “TAG,” “UAA,” “UGA” or “UAG.”

The shortest length of the first region of the primary construct of the IVT polynucleotide of the present invention can be the length of a nucleic acid sequence that is sufficient to encode for a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, or a decapeptide. In another embodiment, the length may be sufficient to encode a peptide of 2-30 amino acids, e.g. 5-30, 10-30, 2-25, 5-25, 10-25, or 10-20 amino acids. The length may be sufficient to encode for a peptide of at least 11, 12, 13, 14, 15, 17, 20, 25 or 30 amino acids, or a peptide that is no longer than 40 amino acids, e.g. no longer than 35, 30, 25, 20, 17, 15, 14, 13, 12, 11 or 10 amino acids. Examples of dipeptides that the polynucleotide sequences can encode or include, but are not limited to, carnosine and anserine. It is understood that the NAV, RNAV or mRNA vaccines of the invention may be translatable and include such first region of a primary construct.

The length of the first region of the primary construct of the IVT polynucleotide encoding the polypeptide of interest of the present invention is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides).

In some embodiments, the IVT polynucleotide includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 7,000, from 1,000 to 10,000, from 1,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, from 1,000 to 100,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 1,500 to 25,000, from 1,500 to 50,000, from 1,500 to 70,000, from 1,500 to 100,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 2,000 to 25,000, from 2,000 to 50,000, from 2,000 to 70,000, and from 2,000 to 100,000).

According to the present invention, the first and second flanking regions of the IVT polynucleotide may range independently from 15-1,000 nucleotides in length (e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, and 900 nucleotides or at least 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1,000 nucleotides).

According to the present invention, the tailing sequence of the IVT polynucleotide may range from absent to 500 nucleotides in length (e.g., at least 60, 70, 80, 90, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, or 500 nucleotides). Where the tailing region is a polyA tail, the length may be determined in units of or as a function of polyA Binding Protein binding. In this embodiment, the polyA tail is long enough to bind at least 4 monomers of PolyA Binding Protein. PolyA Binding Protein monomers bind to stretches of approximately 38 nucleotides. As such, it has been observed that polyA tails of about 80 nucleotides and 160 nucleotides are functional.

According to the present invention, the capping region of the IVT polynucleotide may comprise a single cap or a series of nucleotides forming the cap. In this embodiment the capping region may be from 1 to 10, e.g. 2-9, 3-8, 4-7, 1-5, 5-10, or at least 2, or 10 or fewer nucleotides in length. In some embodiments, the cap is absent.

According to the present invention, the first and second operational regions of the IVT polynucleotide may range from 3 to 40, e.g., 5-30, 10-20, 15, or at least 4, or 30 or fewer nucleotides in length and may comprise, in addition to a Start and/or Stop codon, one or more signal and/or restriction sequences.

In one embodiment, the IVT polynucleotides of the present invention may be structurally modified or chemically modified. When the IVT polynucleotides of the present invention are chemically and/or structurally modified the polynucleotides may be referred to as “modified IVT polynucleotides.”

In one embodiment, if the IVT polynucleotides of the present invention are chemically modified they may have a uniform chemical modification of all or any of the same nucleoside type or a population of modifications produced by mere downward titration of the same starting modification in all or any of the same nucleoside type, or a measured percent of a chemical modification of all any of the same nucleoside type but with random incorporation, such as where all uridines are replaced by a uridine analog, e.g., pseudouridine. In another embodiment, the IVT polynucleotides may have a uniform chemical modification of two, three, or four of the same nucleoside type throughout the entire polynucleotide (such as all uridines and all cytosines, etc. are modified in the same way).

In one embodiment, the IVT polynucleotides of the present invention may include a sequence encoding a self-cleaving peptide, described herein, such as but not limited to the 2A peptide. The polynucleotide sequence of the 2A peptide in the IVT polynucleotide may be modified or codon optimized by the methods described herein and/or are known in the art.

In one embodiment, this sequence may be used to separate the coding region of two or more polypeptides of interest in the IVT polynucleotide.

In one embodiment, the IVT polynucleotide of the present invention may be structurally and/or chemically modified. When chemically modified and/or structurally modified the IVT polynucleotide may be referred to as a “modified IVT polynucleotide.”

In one embodiment, the IVT polynucleotide may encode at least one peptide or polypeptide of interest. In another embodiment, the IVT polynucleotide may encode two or more peptides or polypeptides of interest. Non-limiting examples of peptides or polypeptides of intest include heavy and light chains of antibodies, an enzyme and its substrate, a label and its binding molecule, a second messenger and its enzyme or the components of multimeric proteins or complexes.

Chimeric Polynucleotide Architecture

The chimeric polynucleotides or RNA constructs of the present invention maintain a modular organization similar to IVT polynucleotides, but the chimeric polynucleotides comprise one or more structural and/or chemical modifications or alterations which impart useful properties to the polynucleotide. As such, the chimeric polynucleotides which are modified mRNA molecules of the present invention are termed “chimeric modified mRNA” or “chimeric mRNA.”

It is to be understood that the antigens of the NAVs of the present invention may be encoded by a chimeric polynucleotide, RNA construct, chimeric modified mRNA or chimeric mRNA.

Chimeric polynucleotides have portions or regions which differ in size and/or chemical modification pattern, chemical modification position, chemical modification percent or chemical modification population and combinations of the foregoing.

Examples of parts or regions, where the chimeric polynucleotide functions as an mRNA and encodes a polypeptide of interest include, but are not limited to, untranslated regions (UTRs, such as the 5′ UTR or 3′ UTR), coding regions, cap regions, polyA tail regions, start regions, stop regions, signal sequence regions, and combinations thereof. FIG. 2 illustrates certain embodiments of the chimeric polynucleotides of the invention which may be used as mRNA. FIG. 3 illustrates a schematic of a series of chimeric polynucleotides identifying various patterns of positional modifications and showing regions analogous to those regions of an mRNA polynucleotide. Regions or parts that join or lie between other regions may also be designed to have subregions. These are shown in the figure.

In some embodiments, the chimeric polynucleotides of the invention have a structure comprising Formula I. 5′[A_(n)]_(x-)L1-[B_(o)]_(y-)L2-[C_(p)]_(z)-L3 3′  Formula I

wherein:

each of A and B independently comprise a region of linked nucleosides;

C is an optional region of linked nucleosides;

at least one of regions A, B, or C is positionally modified, wherein said positionally modified region comprises at least two chemically modified nucleosides of one or more of the same nucleoside type of adenosine, thymidine, guanosine, cytidine, or uridine, and wherein at least two of the chemical modifications of nucleosides of the same type are different chemical modifications;

n, o and p are independenty an integer between 15-1000;

x and y are independently 1-20;

z is 0-5;

L1 and L2 are independently optional linker moieties, said linker moieties being either nucleic acid based or non-nucleic acid based; and

L3 is an optional conjugate or an optional linker moiety, said linker moiety being either nucleic acid based or non-nucleic acid based.

In some embodiments the chimeric polynucleotide of Formula I encodes one or more peptides or polypeptides of interest. Such encoded molecules may be encoded across two or more regions.

In another aspect, the invention features a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide has a sequence including Formula II: [A_(n)]-L¹-[B_(o)]  Formula II

wherein each A and B is independently any nucleoside;

n and o are, independently 15 to 1000; and

L¹ has the structure of Formula III:

wherein a, b, c, d, e, and f are each, independently, 0 or 1;

each of R¹, R³, R⁵, and R⁷, is, independently, selected from optionally substituted C₁-C₆ alkylene, optionally substituted C₁-C₆ heteroalkylene, O, S, and NR⁸;

R² and R⁶ are each, independently, selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

R⁴ is optionally substituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀ alkenylene, optionally substituted C₂₋₁₀ alkynylene, optionally substituted C₂-C₉ heterocyclylene, optionally substituted C₆-C₁₂ arylene, optionally substituted C₂-C₁₀₀ polyethylene glycolene, or optionally substituted C₁₋₁₀ heteroalkylene, or a bond linking (R¹)_(a)—(R²)_(b)—(R³)_(c) to (R⁵)_(d)—(R⁶)_(e)—(R⁷)_(f), wherein if c, d, e, f, g, and h are 0, R⁴ is not a bond; and

R⁸ is hydrogen, optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionally substituted C₆-C₁₂ aryl, or optionally substituted C₁-C₇ heteroalkyl;

wherein L¹ is attached to [A_(n)] and [B_(o)] at the sugar of one of the nucleosides (e.g., at the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [A_(n)] and the 5′ position of a five-membered sugar ring or 6′ position of of a six membered sugar ring of a nucleoside of [B_(o)] or at the 5′ position of a five-membered sugar ring or 6′ position of of a six membered sugar ring of a nucleoside of [A_(n)] and the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [B_(o)]).

In some embodiments, at least one of [A_(n)] and [B_(o)] includes the structure of Formula IV:

wherein each of N¹ and N² is independently a nucleobase;

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is, independently, H, halo, hydroxy, thiol, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₂-C₆ heteroalkynyl, optionally substituted amino, azido, or optionally substituted C₆-C₁₀ aryl;

each of g and h is, independently, 0 or 1;

each X¹ and X⁴ is, independently, O, NH, or S;

each X² is independently O or S; and

each X³ is OH or SH, or a salt thereof.

In another aspect, the invention features a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide has a sequence including Formula II: [A_(n)]-L¹-[B_(o)]  Formula II

wherein each A and B is independently any nucleoside;

n and o are, independently 15 to 1000; and

L¹ is a bond or has the structure of Formula III:

wherein a, b, c, d, e, and f are each, independently, 0 or 1;

each of R¹, R³, R⁵, and R⁷, is, independently, selected from optionally substituted C₁-C₆ alkylene, optionally substituted C₁-C₆ heteroalkylene, O, S, and

NR⁸;

R² and R⁶ are each, independently, selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

R⁴ is optionally substituted C₁-C₁₀ alkylene, optionally substituted C₂-C₁₀ alkenylene, optionally substituted C₂₋₁₀ alkynylene, optionally substituted C₂-C₉ heterocyclylene, optionally substituted C₆-C₁₂ arylene, optionally substituted C₂-C₁₀₀ polyethylene glycolene, or optionally substituted C₁₋₁₀ heteroalkylene, or a bond linking (R¹)_(a)—(R²)_(b)—(R³)_(c) to (R⁵)_(d)—(R⁶)_(e)—(R⁷)_(f); and

R⁸ is hydrogen, optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionally substituted C₆-C₁₂ aryl, or optionally substituted C₁-C₇ heteroalkyl;

wherein L¹ is attached to [A_(n)] and [B_(o)] at the sugar of one of the nucleosides (e.g., at the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [A_(n)] and the 5′ position of a five-membered sugar ring or 6′ position of of a six membered sugar ring of a nucleoside of [B_(o)] or at the 5′ position of a five-membered sugar ring or 6′ position of of a six membered sugar ring of a nucleoside of [A_(n)] and the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [B_(o)]).

wherein at least one of [A_(n)] or [B_(o)] includes the structure of Formula IV:

wherein each of N¹ and N² is independently a nucleobase;

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is, independently, H, halo, hydroxy, thiol, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₂-C₆ heteroalkynyl, optionally substituted amino, azido, or optionally substituted C₆-C₁₀ aryl;

each of g and h is, independently, 0 or 1;

each X¹ and X⁴ is, independently, O, NH, or S; and

each X² is independently O or S; and

each X³ is OH or SH, or a salt thereof;

wherein at least one of X¹, X², or X⁴ is NH or S.

In some embodiments, X¹ is NH. In other embodiments, X⁴ is NH. In certain embodiments, X² is S.

In some embodiments, the polynucleotide includes: (a) a coding region; (b) a 5′ UTR including at least one Kozak sequence; (c) a 3′ UTR; and (d) at least one 5′ cap structure. In other embodiments, the polynucleotide further includes (e) a poly-A tail.

In some embodiments, one of the coding region, the 5′ UTR including at least one Kozak sequence, the 3′ UTR, the 5′ cap structure, or the poly-A tail includes [A_(n)]-L¹-[B_(o)].

In other embodiments, one of the coding region, the 5′ UTR including at least one Kozak sequence, the 3′ UTR, the 5′ cap structure, or the poly-A tail includes [A_(n)] and another of the coding region, the 5′ UTR including at least one Kozak sequence, the 3′ UTR, the 5′ cap structure, or the poly-A tail includes [B_(o)].

In certain embodiments, the polynucleotide includes at least one modified nucleoside (e.g., a nucleoside of Table 2).

In some embodiments, R⁴ is optionally substituted C₂₋₉ heterocyclylene, for example, the heterocycle may have the structure:

In certain embodiments, L¹ is attached to [A_(n)] at the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of one of the nucleosides and to [B_(o)] at the 5′ position of a five-membered sugar ring or 6′ position of of a six membered sugar ring of one of the nucleosides.

In some embodiments, the polynucleotide is circular.

In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide includes the structure of Formula V:

This method includes reacting a compound having the structure of Formula VI:

with a compound having the structure of Formula VII:

wherein each of N¹ and N² is, independently, a nucleobase;

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is, independently, H, halo, hydroxy, thiol, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₂-C₆ heteroalkynyl, optionally substituted amino, azido, or optionally substituted C₆-C₁₀ aryl;

each of g and h is, independently, 0 or 1;

each X¹ and X⁴ is, independently, O, NH, or S; and

each X³ is independently OH or SH, or a salt thereof;

each of R¹⁷ and R¹⁹ is, independently, a region of linked nucleosides; and

R¹⁸ is a halogen.

In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide includes the structure of Formula VIII:

This method includes reacting a compound having the structure of Formula IX:

with a compound having the structure of Formula X:

wherein each of N¹ and N² is, independently, a nucleobase;

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is, independently, H, halo, hydroxy, thiol, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₂-C₆ heteroalkynyl, optionally substituted amino, azido, or optionally substituted C₆-C₁₀ aryl;

each of g and h is, independently, 0 or 1;

each X⁴ is, independently, O, NH, or S; and

each X² is independently O or S;

each X³ is independently OH, SH, or a salt thereof;

each of R²⁰ and R²³ is, independently, a region of linked nucleosides; and

each of R²¹ and R²² is, independently, optionally substituted C₁-C₆ alkoxy.

In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherei the polynucleotide includes the structure of Formula XI:

This method includes reacting a compound having the structure of Formula XII:

with a compound having the structure of Formula XIII:

wherein each of N¹ and N² is, independently, a nucleobase;

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is, independently, H, halo, hydroxy, thiol, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₂-C₆ heteroalkynyl, optionally substituted amino, azido, or optionally substituted C₆-C₁₀ aryl;

each of g and h is, independently, 0 or 1;

each X⁴ is, independently, O, NH, or S; and

each X² is independently O or S;

each X³ is independently OH, SH, or a salt thereof;

each of R²⁴ and R²⁶ is, independently, a region of linked nucleosides; and

R²⁵ is optionally substituted C₁-C₆ alkylene or optionally substituted C₁-C₆ heteroalkylene or R²⁵ and the alkynyl group together form optionally substituted cycloalkynyl.

In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide has a sequence including Formula II: [A_(n)]-L¹-[B_(o)]  Formula II

This method includes reacting a compound having the structure of Formula XIV [A_(n]-(R) ¹)_(a)—(R²)_(b)—(R³)_(c)—N₃  Formula XIV with a compound having the structure of Formula XV: R²⁷—(R⁵)_(d)—(R⁶)_(e)—(R⁷)_(f)—[B_(o)]  Formula XV

wherein each A and B is independently any nucleoside;

n and o are, independently 15 to 1000; and

L¹ has the structure of Formula III:

wherein a, b, c, d, e, and f are each, independently, 0 or 1;

wherein each A and B is independently any nucleoside;

n and o are, independently 15 to 1000;

R¹, R³, R⁵, and R⁷ each, independently, is selected from optionally substituted C₁-C₆ alkylene, optionally substituted C₁-C₆ heteroalkylene, O, S, and NR⁸;

R² and R⁶ are each, independently, selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

R⁴ is an optionally substituted triazolene; and

R⁸ is hydrogen, optionally substituted C₁-C₄ alkyl, optionally substituted C₃-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionally substituted C₆-C₁₂ aryl, or optionally substituted C₁-C₇ heteroalkyl; and

R²⁷ is an optionally substituted C₂-C₃ alkynyl or an optionally substituted C₈-C₁₂ cycloalkynyl,

wherein L¹ is attached to [A_(n)] and [B_(o)] at the sugar of one of the nucleosides.

In some embodiments, the optionally substituted triazolene has the structure:

In one embodiment, at least one of the regions of linked nucleosides of A may comprise a sequence of linked nucleosides which can function as a 5′ untranslated region (UTR). The sequence of linked nucleosides may be a natural or synthetic 5′ UTR. As a non-limiting example, the chimeric polynucleotide may encode a polypeptide of interest and the sequence of linked nucleosides of A may encode the native 5′ UTR of a polypeptide encoded by the chimeric polynucleotide or the sequence of linked nucleosides may be a non-heterologous 5′ UTR such as, but not limited to a synthetic UTR.

In another embodiment, at least one of the regions of linked nucleosides of A may be a cap region. The cap region may be located 5′ to a region of linked nucleosides of A functioning as a 5′UTR. The cap region may comprise at least one cap such as, but not limited to, Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, 2-azido-guanosine, Cap2 and Cap4.

In one embodiment, at least one of the regions of linked nucleosdies of B may comprise at least one open reading frame of a nucleic acid sequence. The nucleic acid sequence may be codon optimized and/or comprise at least one modification.

In one embodiment, at least one of the regions of linked nucleosides of C may comprise a sequence of linked nucleosides which can function as a 3′ UTR. The sequence of linked nucleosides may be a natural or synthetic 3′ UTR. As a non-limiting example, the chimeric polynucleotide may encode a polypeptide of interest and the sequence of linked nucleosides of C may encode the native 3′ UTR of a polypeptide encoded by the chimeric polynucleotide or the sequence of linked nucleosides may be a non-heterologous 3′ UTR such as, but not limited to a synthetic UTR.

In one embodiment, at least one of the regions of linked nucleosides of A comprises a sequence of linked nucleosides which functions as a 5′ UTR and at least one of the regions of linked nucleosides of C comprises a sequence of linked nucleosides which functions as a 3′ UTR. In one embodiment, the 5′ UTR and the 3′ UTR may be from the same or different species. In another embodiment, the 5′ UTR and the 3′ UTR may encode the native untranslated regions from different proteins from the same or different species.

FIGS. 4 and 5 provide schematics of a series of chimeric polynucleotides illustrating various patterns of positional modifications based on Formula I as well as those having a blocked or structured 3′ terminus.

Chimeric polynucleotides, including the parts or regions thereof, of the present invention may be classified as hemimers, gapmers, wingmers, or blockmers.

As used herein, a “hemimer” is chimeric polynucleotide comprising a region or part which comprises half of one pattern, percent, position or population of a chemical modification(s) and half of a second pattern, percent, position or population of a chemical modification(s). Chimeric polynucleotides of the present invention may also comprise hemimer subregions. In one embodiment, a part or region is 50% of one and 50% of another.

In one embodiment the entire chimeric polynucleotide can be 50% of one and 50% of the other. Any region or part of any chimeric polynucleotide of the invention may be a hemimer. Types of hemimers include pattern hemimers, population hemimers or position hemimers. By definition, hemimers are 50:50 percent hemimers.

As used herein, a “gapmer” is a chimeric polynucleotide having at least three parts or regions with a gap between the parts or regions. The “gap” can comprise a region of linked nucleosides or a single nucleoside which differs from the chimeric nature of the two parts or regions flanking it. The two parts or regions of a gapmer may be the same or different from each other.

As used herein, a “wingmer” is a chimeric polynucleotide having at least three parts or regions with a gap between the parts or regions. Unlike a gapmer, the two flanking parts or regions surrounding the gap in a wingmer are the same in degree or kind. Such similiarity may be in the length of number of units of different modifications or in the number of modifications. The wings of a wingmer may be longer or shorter than the gap. The wing parts or regions may be 20, 30, 40, 50, 60 70, 80, 90 or 95% greater or shorter in length than the region which comprises the gap.

As used herein, a “blockmer” is a patterned polynucleotide where parts or regions are of equivalent size or number and type of modifications. Regions or subregions in a blockmer may be 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or 500, nuclesides long.

Chimeric polynucleotides, including the parts or regions thereof, of the present invention having a chemical modification pattern are referred to as “pattern chimeras.” Pattern chimeras may also be referred to as blockmers. Pattern chimeras are those polynucleotides having a pattern of modifications within, across or among regions or parts.

Patterns of modifications within a part or region are those which start and stop within a defined region. Patterns of modifcations across a part or region are those patterns which start in on part or region and end in another adjacent part or region. Patterns of modifications among parts or regions are those which begin and end in one part or region and are repeated in a different part or region, which is not necessarily adjacent to the first region or part.

The regions or subregions of pattern chimeras or blockmers may have simple alternating patterns such as ABAB[AB]n where each “A” and each “B” represent different chemical modifications (at at least one of the base, sugar or backbone linker), different types of chemical modifications (e.g., naturally occurring and non-naturally occurring), different percentages of modifications or different populations of modifications. The pattern may repeat n number of times where n=3-300. Further, each A or B can represent from 1-2500 units (e.g., nucleosides) in the pattern. Patterns may also be alternating multiples such as AABBAABB[AABB]n (an alternating double multiple) or AAABBBAAABBB[AAABBB]n (an alternating triple multiple) pattern. The pattern may repeat n number of times where n=3-300.

Different patterns may also be mixed together to form a second order pattern. For example, a single alternating pattern may be combined with a triple alternating pattern to form a second order alternating pattern A′B′. One example would be [ABABAB][AAABBBAAABBB] [ABABAB][AAABBBAAABBB] [ABABAB][AAABBBAAABBB], where [ABABAB] is A′ and [AAABBBAAABBB] is B′. In like fashion, these patterns may be repeated n number of times, where n=3-300.

Patterns may include three or more different modifications to form an ABCABC[ABC]n pattern. These three component patterns may also be multiples, such as AABBCCAABBCC[AABBCC]n and may be designed as combinations with other patterns such as ABCABCAABBCCABCABCAABBCC, and may be higher order patterns.

Regions or subregions of position, percent, and population modifications need not reflect an equal contribution from each modification type. They may form series such as “1-2-3-4”, “1-2-4-8”, where each integer represents the number of units of a particular modification type. Alternatively, they may be odd only, such as “1-3-3-1-3-1-5” or even only “2-4-2-4-6-4-8” or a mixuture of both odd and even number of units such as “1-3-4-2-5-7-3-3-4”.

Pattern chimeras may vary in their chemical modification by degree (such as those described above) or by kind (e.g., different modifications).

Chimeric polynucleotides, including the parts or regions thereof, of the present invention having at least one region with two or more different chemical modifications of two or more nucleoside members of the same nucleoside type (A, C, G, T, or U) are referred to as “positionally modified” chimeras. Positionally modified chimeras are also referred to herein as “selective placement” chimeras or “selective placement polynucleotides”. As the name implies, selective placement refers to the design of polynucleotides which, unlike polynucleotides in the art where the modification to any A, C, G, T or U is the same by virtue of the method of synthesis, can have different modifications to the individual As, Cs, Gs, Ts or Us in a polynucleotide or region thereof. For example, in a positionally modified chimeric polynucleotide, there may be two or more different chemical modifications to any of the nucleoside types of As, Cs, Gs, Ts, or Us. There may also be combinations of two or more to any two or more of the same nucleoside type. For example, a positionally modified or selective placement chimeric polynucleotide may comprise 3 different modifications to the population of adenines in the moleucle and also have 3 different modifications to the population of cytosines in the construct—all of which may have a unique, non-random, placement.

Chimeric polynucleotides, including the parts or regions thereof, of the present invention having a chemical modification percent are referred to as “percent chimeras.” Percent chimeras may have regions or parts which comprise at least 1%, at least 2%, at least 5%, at least 8%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% positional, pattern or population of modifications. Alternatively, the percent chimera may be completely modified as to modification position, pattern, or population. The percent of modification of a percent chimera may be split between naturally occurring and non-naturally occurring modifications.

Chimeric polynucleotides, including the parts or regions thereof, of the present invention having a chemical modification population are referred to as “population chimeras.” A population chimera may comprise a region or part where nucleosides (their base, sugar or backbone linkage, or combination thereof) have a select population of modifications. Such modifications may be selected from functional populations such as modifications which induce, alter or modulate a phenotypic outcome. For example, a functional population may be a population or selection of chemical modifications which increase the level of a cytokine. Other functional populations may individually or collectively function to decrease the level of one or more cytokines. Use of a selection of these like-function modifications in a chimeric polynucleotide would therefore constitute a “functional population chimera.” As used herein, a “functional population chimera” may be one whose unique functional feature is defined by the population of modifications as described above or the term may apply to the overall function of the chimeric polynucleotide itself. For example, as a whole the chimeric polynucleotide may function in a different or superior way as compared to an unmodified or non-chimeric polynucleotide.

It should be noted that polynucleotides which have a uniform chemical modification of all of any of the same nucleoside type or a population of modifications produced by mere downward titration of the same starting modification in all of any of the same nucleoside type, or a measured percent of a chemical modification of all any of the same nucleoside type but with random incorporation, such as where all uridines are replaced by a uridine analog, e.g., pseudouridine, are not considred chimeric. Likewise, polynucleotides having a uniform chemical modification of two, three, or four of the same nucleoside type throughout the entire polynucleotide (such as all uridines and all cytosines, etc. are modified in the same way) are not considered chimeric polynucleotides. One example of a polynucleotide which is not chimeric is the canonical pseudouridine/5-methyl cytosine modified polynucleotide of the prior art. These uniform polynucleotides are arrived at entirely via in vitro transcription (IVT) enzymatic synthesis; and due to the limitations of the synthesizing enzymes, they contain only one kind of modification at the occurrence of each of the same nucleoside type, i.e., adenosine (A), thymidine (T), guanosine (G), cytidine (C) or uradine (U), found in the polynucleotide. Such polynucleotides may be characterized as IVT polynucleotides.

The chimeric polynucleotides of the present invention may be structurally modified or chemically modified. When the chimeric polynucleotides of the present invention are chemically and/or structurally modified the polynucleotides may be referred to as “modified chimeric polynucleotides.”

In some embodiments of the invention, the chimeric polynucleotides may encode two or more peptides or polypeptides of interest. Such peptides or polypeptides of interest include the heavy and light chains of antibodies, an enzyme and its substrate, a label and its binding molecule, a second messenger and its enzyme or the components of multimeric proteins or complexes.

The regions or parts of the chimeric polynucleotides of the present invention may be separated by a linker or spacer moiety. Such linkers or spaces may be nucleic acid based or non-nucleosidic.

In one embodiment, the chimeric polynucleotides of the present invention may include a sequence encoding a self-cleaving peptide described herein, such as, but not limited to, a 2A peptide. The polynucleotide sequence of the 2A peptide in the chimeric polynucleotide may be modified or codon optimized by the methods described herein and/or are known in the art.

Notwithstanding the foregoing, the chimeric polynucleotides of the present invention may comprise a region or part which is not positionally modified or not chimeric as defined herein.

For example, a region or part of a chimeric polynucleotide may be uniformly modified at one ore more A, T, C, G, or U but according to the invention, the polynucleotides will not be uniformly modified throughout the entire region or part.

Regions or parts of chimeric polynucleotides may be from 15-1000 nucleosides in length and a polynucleotide may have from 2-100 different regions or patterns of regions as described herein.

In one embodiment, chimeric polynucleotides encode one or more polypeptides of interest. In another embodiment, the chimeric polynucleotides are substantially non-coding. In another embodiment, the chimeric polynucleotides have both coding and non-coding regions and parts.

FIG. 2 illustrates the design of certain chimeric polynucleotides of the present invention when based on the scaffold of the polynucleotide of FIG. 1. Shown in the figure are the regions or parts of the chimeric polynucleotides where patterned regions represent those regions which are positionally modified and open regions illustrate regions which may or may not be modified but which are, when modified, uniformly modified. Chimeric polynucleotides of the present invention may be completely positionally modified or partially positionally modified. They may also have subregions which may be of any pattern or design. Shown in FIG. 2 are a chimeric subregion and a hemimer subregion.

In one embodiment, the shortest length of a region of the chimeric polynucleotide of the present invention encoding a peptide can be the length that is sufficient to encode for a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, or a decapeptide. In another embodiment, the length may be sufficient to encode a peptide of 2-30 amino acids, e.g. 5-30, 10-30, 2-25, 5-25, 10-25, or 10-20 amino acids. The length may be sufficient to encode for a peptide of at least 11, 12, 13, 14, 15, 17, 20, 25 or 30 amino acids, or a peptide that is no longer than 40 amino acids, e.g. no longer than 35, 30, 25, 20, 17, 15, 14, 13, 12, 11 or 10 amino acids. Examples of dipeptides that the polynucleotide sequences can encode or include, but are not limited to, carnosine and anserine.

In one embodiment, the length of a region of the chimeric polynucleotide of the present invention encoding the peptide or polypeptide of interest is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides). As used herein, such a region may be referred to as a “coding region” or “region encoding.”

In some embodiments, the chimeric polynucleotide includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 7,000, from 1,000 to 10,000, from 1,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, from 1,000 to 100,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 1,500 to 25,000, from 1,500 to 50,000, from 1,500 to 70,000, from 1,500 to 100,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 2,000 to 25,000, from 2,000 to 50,000, from 2,000 to 70,000, and from 2,000 to 100,000).

According to the present invention, regions or subregions of the chimeric polynucleotides may also range independently from 15-1,000 nucleotides in length (e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900 and 950 nucleotides or at least 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 and 1,000 nucleotides).

According to the present invention, regions or subregions of chimeric polynucleotides may range from absent to 500 nucleotides in length (e.g., at least 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, or 500 nucleotides). Where the region is a polyA tail, the length may be determined in units of or as a function of polyA Binding Protein binding. In this embodiment, the polyA tail is long enough to bind at least 4 monomers of PolyA Binding Protein. PolyA Binding Protein monomers bind to stretches of approximately 38 nucleotides. As such, it has been observed that polyA tails of about 80 nucleotides to about 160 nucleotides are functional. The chimeric polynucleotides of the present invention which function as an mRNA need not comprise a polyA tail.

According to the present invention, chimeric polynucleotides which function as an mRNA may have a capping region. The capping region may comprise a single cap or a series of nucleotides forming the cap. In this embodiment the capping region may be from 1 to 10, e.g. 2-9, 3-8, 4-7, 1-5, 5-10, or at least 2, or 10 or fewer nucleotides in length. In some embodiments, the cap is absent.

The present invention contemplates chimeric polynucleotides which are circular or cyclic. As the name implies circular polynucleotides are circular in nature meaning that the termini are joined in some fashion, whether by ligation, covalent bond, common association with the same protein or other molecule or complex or by hybridization. Any of the cicular polynucleotides as taught in for example U.S. Provisional Application No. 61/873,010 filed Sep. 3, 2013, the contents of which are incorporated herein by reference in their entirety, may be made chimeric according to the present invention.

Chimeric polynucleotides, formulations and compositions comprising chimeric polynucleotides, and methods of making, using and administering chimeric polynucleotides are also described in U.S. Provisional Application No. 61/873,034, filed Sep. 3, 2013, entitled Chimeric Polynucleotides, and U.S. Provisional Application No. 61/877,582, filed Sep. 13, 2013, entitled Chimeric Polynucleotides; each of which is incorporated by reference in its entirety.

Circular Polynculeotide Architecture

The present invention contemplates polynucleotides which are circular or cyclic. As the name implies circular polynucleotides are circular in nature meaning that the termini are joined in some fashion, whether by ligation, covalent bond, common association with the same protein or other molecule or complex or by hybridization. Any of the cicular polynucleotides as taught in for example U.S. Provisional Application No. 61/873,010 filed Sep. 3, 2013, the contents of which are incorporated herein by reference in their entirety.

Circular polynucleotides of the present invention may be designed according to the circular RNA construct scaffolds shown in FIGS. 6-12. Such polynucleotides are cicular polynucleotides or circular constructs.

The circular polynucleotides or circPs of the present invention which encode at least one peptide or polypeptide of interest are known as circular RNAs or circRNA. The antigens of the NAVs of the present invention may be encoded by one or more circular RNAs or circRNAs.

As used herein, “circular RNA” or “circRNA” means a circular polynucleotide that can encode at least one peptide or polypeptide of interest. The circPs of the present invention which comprise at least one sensor sequence and do not encode a peptide or polypeptide of interest are known as circular sponges or circSP. As used herein, “circular sponges,” “circular polynucleotide sponges” or “circSP” means a circular polynucleotide which comprises at least one sensor sequence and does not encode a polypeptide of interest. Such noncoding polynucleotides may be useful in the NAVs of the present invention as noncoding nucleic acids may function as an antigenic composition.

As used herein, “sensor sequence” means a receptor or pseudo-receptor for endogenous nucleic acid binding molecules. Non-limiting examples of sensor sequences include, microRNA binding sites, microRNA seed sequences, microRNA binding sites without the seed sequence, transcription factor binding sites and artificial binding sites engineered to act as pseudo-receptors and portions and fragments thereof.

The circPs of the present invention which comprise at least one sensor sequence and encode at least one peptide or polypeptide of interest are known as circular RNA sponges or circRNA-SP. As used herein, “circular RNA sponges” or “circRNA-SP” means a circular polynucleotide which comprises at least one sensor sequence and at least one region encoding at least one peptide or polypeptide of interest.

FIG. 6A shows a representative circular construct 200 of the circular polynucleotides of the present invention. As used herein, the term “circular construct” refers to a circular polynucleotide transcript which may act substantiatlly similar to and have properties of a RNA molecule. In one embodiment the circular construct acts as an mRNA. If the circular construct encodes one or more peptides or polypeptides of interest (e.g., a circRNA or circRNA-SP) then the polynucleotide transcript retains sufficient structural and/or chemical features to allow the polypeptide of interest encoded therein to be translated. Circular constructs may be polynucleotides of the invention. When structurally or chemically modified, the construct may be referred to as a modified circP, modified circSP, modified circRNA or modified circRNA-SP.

Returning to FIG. 6A, the circular construct 200 here contains a first region of linked nucleotides 202 that is flanked by a first flanking region 204 and a second flanking region 206. As used herein, the “first region” may be referred to as a “coding region,” a “non-coding region” or “region encoding” or simply the “first region.” In one embodiment, this first region may comprise nucleotides such as, but is not limited to, encoding at leaset one peptide or polypeptide of interest and/or nucleotides encoding a sensor region. The peptide or polypeptide of interest may comprise at its 5′ terminus one or more signal peptide sequences encoded by a signal peptide sequence region 203. The first flanking region 204 may comprise a region of linked nucleosides or portion thereof which may act similiarly to an untranslated region (UTR) in an mRNA and/or DNA sequence. The first flanking region may also comprise a region of polarity 208. The region of polarity 208 may include an IRES sequence or portion thereof. As a non-limiting example, when linearlized this region may be split to have a first portion be on the 5′ terminus of the first region 202 and second portion be on the 3′ terminus of the first region 202. The second flanking region 206 may comprise a tailing sequence region 210 and may comprise a region of linked nucleotides or portion thereof 212 which may act similiarly to a UTR in an mRNA and/or DNA.

Bridging the 5′ terminus of the first region 202 and the first flanking region 104 is a first operational region 205. In one embodiment, this operational region may comprise a start codon. The operational region may alternatively comprise any translation initiation sequence or signal including a start codon.

Bridging the 3′ terminus of the first region 202 and the second flanking region 106 is a second operational region 207. Traditionally this operational region comprises a stop codon. The operational region may alternatively comprise any translation initiation sequence or signal including a stop codon. According to the present invention, multiple serial stop codons may also be used. In one embodiment, the operation region of the present invention may comprise two stop codons. The first stop codon may be “TGA” or “UGA” and the second stop codon may be selected from the group consisting of “TAA,” “TGA,” “TAG,” “UAA,” “UGA” or “UAG.”

Turning to FIG. 6B, at least one non-nucleic acid moiety 201 may be used to prepare a circular construct 200 where the non-nucleic acid moiety 201 is used to bring the first flanking region 204 near the second flanking region 206. Non-limiting examples of non-nucleic acid moieties which may be used in the present invention are described herein. The circular construct 200 may comprise more than one non-nucleic acid moiety wherein the additional non-nucleic acid moeities may be heterologous or homologous to the first non-nucleic acid moiety.

Turning to FIG. 7A, the first region of linked nucleosides 202 may comprise a spacer region 214. This spacer region 214 may be used to separate the first region of linked nucleosides 202 so that the circular construct can include more than one open reading frame, non-coding region or an open reading frame and a non-coding region.

Turning to FIG. 7B, the second flanking region 206 may comprise one or more sensor regions 216 in the the 3′UTR 212. These sensor sequences as discussed herein operate as pseudo-receptors (or binding sites) for ligands of the local microenvironment of the circular construct. For example, microRNA bindng sites or miRNA seeds may be used as sensors such that they function as pseudoreceptors for any microRNAs present in the environment of the circular polynucleotide. As shown in FIG. 9, the one or more sensor regions 216 may be separated by a spacer region 214.

As shown in FIG. 8A, a circular construct 200, which includes one or more sensor regions 216, may also include a spacer region 214 in the first region of linked nucleosides 202. As discussed above for FIG. 7, this spacer region 214 may be used to separate the first region of linked nucleosides 202 so that the circular construct can include more than one open reading frame and/or more than one non-coding region.

Turning to FIG. 8B, a circular construct 200 may be a non-coding construct known as a circSP comprising at least one non-coding region such as, but not limited to, a sensor region 216. Each of the sensor regions 216 may include, but are not limited to, a miR sequence, a miR seed, a miR binding site and/or a miR sequence without the seed.

Turning to FIG. 9, at least one non-nucleic acid moiety 201 may be used to prepare a circular construct 200 which is a non-coding construct. The circular construct 200 which is a non-coding construct may comprise more than one non-nucleic acid moiety wherein the additional non-nucleic acid moeities may be heterologous or homologous to the first non-nucleic acid moiety.

Circular polynucleotides, formulations and compositions comprising circular polynucleotides, and methods of making, using and administering circular polynucleotides are also described in U.S. Provisional Application No. 61/873,010, filed Sep. 3, 2013, entitled Circular Polynucleotides, and U.S. Provisional Application No. 61/877,527, filed Sep. 13, 2013, entitled Circular Polynucleotides; each of which is incorporated by reference in its entirety.

Multimers of Polynucleotides

According to the present invention, multiple distinct chimeric polynucleotides and/or IVT polynucleotides may be linked together through the 3′-end using nucleotides which are modified at the 3′-terminus. Chemical conjugation may be used to control the stoichiometry of delivery into cells. For example, the glyoxylate cycle enzymes, isocitrate lyase and malate synthase, may be supplied into cells at a 1:1 ratio to alter cellular fatty acid metabolism. This ratio may be controlled by chemically linking chimeric polynucleotides and/or IVT polynucleotides using a 3′-azido terminated nucleotide on one polynucleotides species and a C5-ethynyl or alkynyl-containing nucleotide on the opposite polynucleotide species. The modified nucleotide is added post-transcriptionally using terminal transferase (New England Biolabs, Ipswich, Mass.) according to the manufacturer's protocol. After the addition of the 3′-modified nucleotide, the two polynucleotides species may be combined in an aqueous solution, in the presence or absence of copper, to form a new covalent linkage via a click chemistry mechanism as described in the literature.

In another example, more than two chimeric polynucleotides and/or IVT polynucleotides may be linked together using a functionalized linker molecule. For example, a functionalized saccharide molecule may be chemically modified to contain multiple chemical reactive groups (SH—, NH₂—, N₃, etc . . . ) to react with the cognate moiety on a 3′-functionalized mRNA molecule (i.e., a 3′-maleimide ester, 3′-NHS-ester, alkynyl). The number of reactive groups on the modified saccharide can be controlled in a stoichiometric fashion to directly control the stoichiometric ratio of conjugated chimeric polynucleotides and/or IVT polynucleotides.

In one embodiment, the chimeric polynucleotides and/or IVT polynucleotides may be linked together in a pattern. The pattern may be a simple alternating pattern such as CD[CD]_(x) where each “C” and each “D” represent a chimeric polynucleotide, IVT polynucleotide, different chimeric polynucleotides or different IVT polynucleotides. The pattern may repeat x number of times, where x=1-300. It is to be understood that the antigens of the NAVs of the present invention may be encoded by such linked polynucleotides, as described herein. Paterns may also be alternating multiples such as CCDD[CCDD]_(x) (an alternating double multiple) or CCCDDD[CCCDDD]_(x) (an alternating triple multiple) pattern. The alternating double multiple or alternating triple multiple may repeat x number of times, where x=1-300.

Conjugates and Combinations of Polynucleotides

In order to further enhance protein production, polynucleotides of the present invention can be designed to be conjugated to other polynucleotides, dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG]₂, polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport/absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases, proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a cancer cell, endothelial cell, or bone cell, hormones and hormone receptors, non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, or a drug.

In a preferred embodiment, the polynucleotides of the present invention which encode an antigen are conjugated to one or more dendritic cell markers.

Conjugation may result in increased stability and/or half life and may be particularly useful in targeting the polynucleotides to specific sites in the cell, tissue or organism.

According to the present invention, the polynucleotides may be administered with, conjugated to or further encode one or more of RNAi agents, siRNAs, shRNAs, miRNAs, miRNA binding sites, antisense RNAs, ribozymes, catalytic DNA, tRNA, RNAs that induce triple helix formation, aptamers or vectors, and the like.

Bifunctional Polynucleotides

In one embodiment of the invention NAVs may comprise bifunctional polynucleotides (e.g., bifunctional IVT polynucleotides, bifunctional chimeric polynucleotides or bifunctional circular polynucleotides). As the name implies, bifunctional polynucleotides are those having or capable of at least two functions. These molecules may also by convention be referred to as multi-functional. It is to be understood that the NAV polynucleotides of the present invention may be conjugated to other molecules or agents, as described supra.

The multiple functionalities of bifunctional polynucleotides may be encoded by the NAV (the function may not manifest until the encoded product is translated) or may be a property of the polynucleotide itself. It may be structural or chemical. Bifunctional modified polynucleotides may comprise a function that is covalently or electrostatically associated with the polynucleotides. Further, the two functions may be provided in the context of a complex of a chimeric polynucleotide and another molecule.

Noncoding Polynucleotides

As described herein, provided are polynucleotides having sequences that are partially or substantially not translatable, e.g., having a noncoding region. As one non-limiting example, the noncoding region may be the first region of the IVT polynucleotide or the circular polynucleotide. Alternatively, the noncoding region may be a region other than the first region. As another non-limiting example, the noncoding region may be the A, B and/or C region of the chimeric polynucleotide.

Such molecules are generally not translated, but can exert an effect on the immune response or protein production by one or more of binding to and sequestering one or more translational machinery components such as a ribosomal protein or a transfer RNA (tRNA), thereby effectively reducing protein expression in the cell or modulating one or more pathways or cascades in a cell which in turn alters protein levels. The polynucleotide may contain or encode one or more long noncoding RNA (lncRNA, or lincRNA) or portion thereof, a small nucleolar RNA (sno-RNA), micro RNA (miRNA), small interfering RNA (siRNA) or Piwi-interacting RNA (piRNA). Examples of such lncRNA molecules and RNAi constructs designed to target such lncRNA any of which may be encoded in the polynucleotides are taught in International Publication, WO2012/018881 A2, the contents of which are incorporated herein by reference in their entirety.

According to the present invention, the polynucleotide may be designed to encode one or more polypeptides of interest or fragments thereof. Such polypeptide of interest may include, but is not limited to, whole polypeptides, a plurality of polypeptides or fragments of polypeptides, which independently may be encoded by one or more regions or parts or the whole of a polynucleotide. As used herein, the term “polypeptides of interest” refer to any polypeptide which is selected to be encoded within, or whose function is affected by, the polnucleotides of the present invention. Any of the peptides or polypetides of the invention may be antigenic.

As used herein, “polypeptide” means a polymer of amino acid residues (natural or unnatural) linked together most often by peptide bonds. The term, as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function. In one embodiment, the polypeptides of interest are antigens encoded by the polynucleotides as described herein.

In some instances the polypeptide encoded is smaller than about 50 amino acids and the polypeptide is then termed a peptide. If the polypeptide is a peptide, it will be at least about 2, 3, 4, or at least 5 amino acid residues long. Thus, polypeptides include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing. A polypeptide may be a single molecule or may be a multi-molecular complex such as a dimer, trimer or tetramer. They may also comprise single chain or multichain polypeptides such as antibodies or insulin and may be associated or linked. Most commonly disulfide linkages are found in multichain polypeptides. The term polypeptide may also apply to amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid.

The term “polypeptide variant” refers to molecules which differ in their amino acid sequence from a native or reference sequence. The amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. Ordinarily, variants will possess at least about 50% identity (homology) to a native or reference sequence, and preferably, they will be at least about 80%, more preferably at least about 90% identical (homologous) to a native or reference sequence.

In some embodiments “variant mimics” are provided. As used herein, the term “variant mimic” is one which contains one or more amino acids which would mimic an activated sequence. For example, glutamate may serve as a mimic for phosphoro-threonine and/or phosphoro-serine. Alternatively, variant mimics may result in deactivation or in an inactivated product containing the mimic, e.g., phenylalanine may act as an inactivating substitution for tyrosine; or alanine may act as an inactivating substitution for serine.

“Homology” as it applies to amino acid sequences is defined as the percentage of residues in the candidate amino acid sequence that are identical with the residues in the amino acid sequence of a second sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology. Methods and computer programs for the alignment are well known in the art. It is understood that homology depends on a calculation of percent identity but may differ in value due to gaps and penalties introduced in the calculation.

By “homologs” as it applies to polypeptide sequences means the corresponding sequence of other species having substantial identity to a second sequence of a second species.

“Analogs” is meant to include polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting polypeptide.

The present invention contemplates several types of compositions which are polypeptide based including variants and derivatives. These include substitutional, insertional, deletion and covalent variants and derivatives. The term “derivative” is used synonymously with the term “variant” but generally refers to a molecule that has been modified and/or changed in any way relative to a reference molecule or starting molecule.

As such, polynucleotides encoding peptides or polypeptides containing substitutions, insertions and/or additions, deletions and covalent modifications with respect to reference sequences, in particular the polypeptide sequences disclosed herein, are included within the scope of this invention. For example, sequence tags or amino acids, such as one or more lysines, can be added to the peptide sequences of the invention (e.g., at the N-terminal or C-terminal ends). Sequence tags can be used for peptide purification or localization. Lysines can be used to increase peptide solubility or to allow for biotinylation. Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C-terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble, or linked to a solid support.

“Substitutional variants” when referring to polypeptides are those that have at least one amino acid residue in a native or starting sequence removed and a different amino acid inserted in its place at the same position. The substitutions may be single, where only one amino acid in the molecule has been substituted, or they may be multiple, where two or more amino acids have been substituted in the same molecule.

As used herein the term “conservative amino acid substitution” refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine and leucine for another non-polar residue. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, the substitution of a basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions. Examples of non-conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and/or a polar residue for a non-polar residue.

“Insertional variants” when referring to polypeptides are those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a native or starting sequence. “Immediately adjacent” to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid.

“Deletional variants” when referring to polypeptides are those with one or more amino acids in the native or starting amino acid sequence removed. Ordinarily, deletional variants will have one or more amino acids deleted in a particular region of the molecule.

“Covalent derivatives” when referring to polypeptides include modifications of a native or starting protein with an organic proteinaceous or non-proteinaceous derivatizing agent, and/or post-translational modifications. Covalent modifications are traditionally introduced by reacting targeted amino acid residues of the protein with an organic derivatizing agent that is capable of reacting with selected side-chains or terminal residues, or by harnessing mechanisms of post-translational modifications that function in selected recombinant host cells. The resultant covalent derivatives are useful in programs directed at identifying residues important for biological activity, for immunoassays, or for the preparation of anti-protein antibodies for immunoaffinity purification of the recombinant glycoprotein. Such modifications are within the ordinary skill in the art and are performed without undue experimentation.

Certain post-translational modifications are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues may be present in the polypeptides produced in accordance with the present invention.

Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco, pp. 79-86 (1983)).

“Features” when referring to polypeptides are defined as distinct amino acid sequence-based components of a molecule. Features of the polypeptides encoded by the polynucleotides of the present invention include surface manifestations, local conformational shape, folds, loops, half-loops, domains, half-domains, sites, termini or any combination thereof.

As used herein when referring to polypeptides the term “surface manifestation” refers to a polypeptide based component of a protein appearing on an outermost surface.

As used herein when referring to polypeptides the term “local conformational shape” means a polypeptide based structural manifestation of a protein which is located within a definable space of the protein.

As used herein when referring to polypeptides the term “fold” refers to the resultant conformation of an amino acid sequence upon energy minimization. A fold may occur at the secondary or tertiary level of the folding process. Examples of secondary level folds include beta sheets and alpha helices. Examples of tertiary folds include domains and regions formed due to aggregation or separation of energetic forces. Regions formed in this way include hydrophobic and hydrophilic pockets, and the like.

As used herein the term “turn” as it relates to protein conformation means a bend which alters the direction of the backbone of a peptide or polypeptide and may involve one, two, three or more amino acid residues.

As used herein when referring to polypeptides the term “loop” refers to a structural feature of a polypeptide which may serve to reverse the direction of the backbone of a peptide or polypeptide. Where the loop is found in a polypeptide and only alters the direction of the backbone, it may comprise four or more amino acid residues. Oliva et al. have identified at least 5 classes of protein loops (J. Mol Biol 266 (4): 814-830; 1997). Loops may be open or closed. Closed loops or “cyclic” loops may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids between the bridging moieties. Such bridging moieties may comprise a cysteine-cysteine bridge (Cys-Cys) typical in polypeptides having disulfide bridges or alternatively bridging moieties may be non-protein based such as the dibromozylyl agents used herein.

As used herein when referring to polypeptides the term “half-loop” refers to a portion of an identified loop having at least half the number of amino acid resides as the loop from which it is derived. It is understood that loops may not always contain an even number of amino acid residues. Therefore, in those cases where a loop contains or is identified to comprise an odd number of amino acids, a half-loop of the odd-numbered loop will comprise the whole number portion or next whole number portion of the loop (number of amino acids of the loop/2+/−0.5 amino acids).

For example, a loop identified as a 7 amino acid loop could produce half-loops of 3 amino acids or 4 amino acids (7/2=3.5+1−0.5 being 3 or 4).

As used herein when referring to polypeptides the term “domain” refers to a motif of a polypeptide having one or more identifiable structural or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions).

As used herein when referring to polypeptides the term “half-domain” means a portion of an identified domain having at least half the number of amino acid resides as the domain from which it is derived. It is understood that domains may not always contain an even number of amino acid residues. Therefore, in those cases where a domain contains or is identified to comprise an odd number of amino acids, a half-domain of the odd-numbered domain will comprise the whole number portion or next whole number portion of the domain (number of amino acids of the domain/2+/−0.5 amino acids). For example, a domain identified as a 7 amino acid domain could produce half-domains of 3 amino acids or 4 amino acids (7/2=3.5+1−0.5 being 3 or 4). It is also understood that sub-domains may be identified within domains or half-domains, these subdomains possessing less than all of the structural or functional properties identified in the domains or half domains from which they were derived. It is also understood that the amino acids that comprise any of the domain types herein need not be contiguous along the backbone of the polypeptide (i.e., nonadjacent amino acids may fold structurally to produce a domain, half-domain or subdomain).

As used herein when referring to polypeptides the terms “site” as it pertains to amino acid based embodiments is used synonymously with “amino acid residue” and “amino acid side chain.” A site represents a position within a peptide or polypeptide that may be modified, manipulated, altered, derivatized or varied within the polypeptide based molecules of the present invention.

As used herein the terms “termini” or “terminus” when referring to polypeptides refers to an extremity of a peptide or polypeptide. Such extremity is not limited only to the first or final site of the peptide or polypeptide but may include additional amino acids in the terminal regions. The polypeptide based molecules of the present invention may be characterized as having both an N-terminus (terminated by an amino acid with a free amino group (NH2)) and a C-terminus (terminated by an amino acid with a free carboxyl group (COOH)). Proteins of the invention are in some cases made up of multiple polypeptide chains brought together by disulfide bonds or by non-covalent forces (multimers, oligomers). These sorts of proteins will have multiple N- and C-termini. Alternatively, the termini of the polypeptides may be modified such that they begin or end, as the case may be, with a non-polypeptide based moiety such as an organic conjugate.

Once any of the features have been identified or defined as a desired component of a polypeptide to be encoded by a polynucleotide of the invention, any of several manipulations and/or modifications of these features may be performed by moving, swapping, inverting, deleting, randomizing or duplicating. Furthermore, it is understood that manipulation of features may result in the same outcome as a modification to the molecules of the invention. For example, a manipulation which involved deleting a domain would result in the alteration of the length of a molecule just as modification of a nucleic acid to encode less than a full length molecule would.

Modifications and manipulations can be accomplished by methods known in the art such as, but not limited to, site directed mutagenesis or a priori incorporation during chemical synthesis. The resulting modified molecules may then be tested for activity using in vitro or in vivo assays such as those described herein or any other suitable screening assay known in the art.

According to the present invention, the polypeptides may comprise a consensus sequence which is discovered through rounds of experimentation. As used herein a “consensus” sequence is a single sequence which represents a collective population of sequences allowing for variability at one or more sites.

As recognized by those skilled in the art, protein fragments, functional protein domains, and homologous proteins are also considered to be within the scope of polypeptides of interest of this invention. For example, provided herein is any protein fragment (meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical) of a reference protein 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or greater than 100 amino acids in length. In another example, any protein that includes a stretch of about 20, about 30, about 40, about 50, or about 100 amino acids which are about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% identical to any of the sequences described herein can be utilized in accordance with the invention. In certain embodiments, a polypeptide to be utilized in accordance with the invention includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mutations as shown in any of the sequences provided or referenced herein.

In one embodiment, at least one polypeptide of interest may be an antigen or fragment thereof, or any component of a ribonucleic acid vaccine.

Reference molecules (polypeptides or polynucleotides) may share a certain identity with the designed molecules (polypeptides or polynucleotides). The term “identity” as known in the art, refers to a relationship between the sequences of two or more peptides, polypeptides or polynucleotides, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between them as determined by the number of matches between strings of two or more amino acid residues or nucleosides. Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”). Identity of related peptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, N.Y., 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, N.Y., 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, N.J., 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M. Stockton Press, N.Y., 1991; and Carillo et al., SIAM J. Applied Math. 48, 1073 (1988).

In some embodiments, the encoded polypeptide variant may have the same or a similar activity as the reference polypeptide. Alternatively, the variant may have an altered activity (e.g., increased or decreased) relative to a reference polypeptide. Generally, variants of a particular polynucleotide or polypeptide of the invention will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% but less than 100% sequence identity to that particular reference polynucleotide or polypeptide as determined by sequence alignment programs and parameters described herein and known to those skilled in the art. Such tools for alignment include those of the BLAST suite (Stephen F. Altschul, Thomas L. Madden, Alejandro A. Schäffer, Jinghui Zhang, Zheng Zhang, Webb Miller, and David J. Lipman (1997), “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs”, Nucleic Acids Res. 25:3389-3402.) Other tools are described herein, specifically in the definition of “Identity.”

Default parameters in the BLAST algorithm include, for example, an expect threshold of 10, Word size of 28, Match/Mismatch Scores 1, −2, Gap costs Linear. Any filter can be applied as well as a selection for species specific repeats, e.g., Homo sapiens.

Cell-Penetrating Polypeptides

The polynucleotides disclosed herein (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention), may also encode one or more cell-penetrating polypeptides. As used herein, “cell-penetrating polypeptide” or CPP refers to a polypeptide which may facilitate the cellular uptake of molecules. A cell-penetrating polypeptide of the present invention may contain one or more detectable labels. The polypeptides may be partially labeled or completely labeled throughout. The polynucleotides may encode the detectable label completely, partially or not at all. The cell-penetrating peptide may also include a signal sequence. As used herein, a “signal sequence” refers to a sequence of amino acid residues bound at the amino terminus of a nascent protein during protein translation. The signal sequence may be used to signal the secretion of the cell-penetrating polypeptide.

In one embodiment, the polynucleotides may also encode a fusion protein. The fusion protein may be created by operably linking a charged protein to a therapeutic protein. As used herein, “operably linked” refers to the therapeutic protein and the charged protein being connected in such a way to permit the expression of the complex when introduced into the cell. As used herein, “charged protein” refers to a protein that carries a positive, negative or overall neutral electrical charge. Preferably, the therapeutic protein may be covalently linked to the charged protein in the formation of the fusion protein. The ratio of surface charge to total or surface amino acids may be approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9.

The cell-penetrating polypeptide encoded by the polynucleotides may form a complex after being translated. The complex may comprise a charged protein linked, e.g. covalently linked, to the cell-penetrating polypeptide. “Therapeutic protein” refers to a protein that, when administered to a cell has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.

In one embodiment, the cell-penetrating polypeptide may comprise a first domain and a second domain. The first domain may comprise a supercharged polypeptide. The second domain may comprise a protein-binding partner. As used herein, “protein-binding partner” includes, but is not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides. The cell-penetrating polypeptide may further comprise an intracellular binding partner for the protein-binding partner. The cell-penetrating polypeptide may be capable of being secreted from a cell where the polynucleotides may be introduced. The cell-penetrating polypeptide may also be capable of penetrating the first cell.

In a further embodiment, the cell-penetrating polypeptide is capable of penetrating a second cell. The second cell may be from the same area as the first cell, or it may be from a different area. The area may include, but is not limited to, tissues and organs. The second cell may also be proximal or distal to the first cell.

In one embodiment, the polynucleotides may encode a cell-penetrating polypeptide which may comprise a protein-binding partner. The protein binding partner may include, but is not limited to, an antibody, a supercharged antibody or a functional fragment. The polynucleotides may be introduced into the cell where a cell-penetrating polypeptide comprising the protein-binding partner is introduced.

Anti-Microbial and Anti-Viral Polypeptides

The polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be designed to encode, or be co-administered with, a polynucleotide encoding one or more antimicrobial peptides (AMP) or antiviral peptides (AVP). AMPs and AVPs have been isolated and described from a wide range of animals such as, but not limited to, microorganisms, invertebrates, plants, amphibians, birds, fish, and mammals (Wang et al., Nucleic Acids Res. 2009; 37 (Database issue):D933-7). For example, anti-microbial polypeptides are described in Antimicrobial Peptide Database (http://aps.unmc.edu/AP/main.php; Wang et al., Nucleic Acids Res. 2009; 37 (Database issue):D933-7), CAMP: Collection of Anti-Microbial Peptides (http://www.bicnirrh.res.in/antimicrobial/); Thomas et al., Nucleic Acids Res. 2010; 38 (Database issue):D774-80), U.S. Pat. Nos. 5,221,732, 5,447,914, 5,519,115, 5,607,914, 5,714,577, 5,734,015, 5,798,336, 5,821,224, 5,849,490, 5,856,127, 5,905,187, 5,994,308, 5,998,374, 6,107,460, 6,191,254, 6,211,148, 6,300,489, 6,329,504, 6,399,370, 6,476,189, 6,478,825, 6,492,328, 6,514,701, 6,573,361, 6,573,361, 6,576,755, 6,605,698, 6,624,140, 6,638,531, 6,642,203, 6,653,280, 6,696,238, 6,727,066, 6,730,659, 6,743,598, 6,743,769, 6,747,007, 6,790,833, 6,794,490, 6,818,407, 6,835,536, 6,835,713, 6,838,435, 6,872,705, 6,875,907, 6,884,776, 6,887,847, 6,906,035, 6,911,524, 6,936,432, 7,001,924, 7,071,293, 7,078,380, 7,091,185, 7,094,759, 7,166,769, 7,244,710, 7,314,858, and 7,582,301, the contents of which are incorporated by reference in their entirety.

The anti-microbial polypeptides described herein may block cell fusion and/or viral entry by one or more enveloped viruses (e.g., HIV, HCV). For example, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the transmembrane subunit of a viral envelope protein, e.g., HIV-1 gp120 or gp41. The amino acid and nucleotide sequences of HIV-1 gp120 or gp41 are described in, e.g., Kuiken et al., (2008). “HIV Sequence Compendium,” Los Alamos National Laboratory.

In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence. In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, or 100% sequence homology to the corresponding viral protein sequence.

In other embodiments, the anti-microbial polypeptide may comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a capsid binding protein. In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, or 100% sequence homology to the corresponding sequence of the capsid binding protein.

The anti-microbial polypeptides described herein may block protease dimerization and inhibit cleavage of viral proproteins (e.g., HIV Gag-pol processing) into functional proteins thereby preventing release of one or more enveloped viruses (e.g., HIV, HCV). In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence.

In other embodiments, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a protease binding protein. In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding sequence of the protease binding protein.

The anti-microbial polypeptides described herein can include an in vitro-evolved polypeptide directed against a viral pathogen.

Anti-Microbial Polypeptides

Anti-microbial polypeptides (AMPs) are small peptides of variable length, sequence and structure with broad spectrum activity against a wide range of microorganisms including, but not limited to, bacteria, viruses, fungi, protozoa, parasites, prions, and tumor/cancer cells. (See, e.g., Zaiou, J Mol Med, 2007; 85:317; herein incorporated by reference in its entirety). It has been shown that AMPs have broad-spectrum of rapid onset of killing activities, with potentially low levels of induced resistance and concomitant broad anti-inflammatory effects.

In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be under 10 kDa, e.g., under 8 kDa, 6 kDa, 4 kDa, 2 kDa, or 1 kDa. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, about 25 to about 100 amino acids, about 50 to about 100 amino acids, or about 75 to about 100 amino acids. In certain embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may consist of from about 15 to about 45 amino acids. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is substantially cationic.

In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be substantially amphipathic. In certain embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be substantially cationic and amphipathic. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic and cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytotoxic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic and cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide may be cytostatic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide may be cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In certain embodiments, the anti-microbial polypeptide may be cytostatic and cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide may be cytotoxic to a tumor or cancer cell (e.g., a human tumor and/or cancer cell). In some embodiments, the anti-microbial polypeptide may be cytostatic to a tumor or cancer cell (e.g., a human tumor and/or cancer cell). In certain embodiments, the anti-microbial polypeptide may be cytotoxic and cytostatic to a tumor or cancer cell (e.g., a human tumor or cancer cell). In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be a secreted polypeptide.

In some embodiments, the anti-microbial polypeptide comprises or consists of a defensin. Exemplary defensins include, but are not limited to, α-defensins (e.g., neutrophil defensin 1, defensin alpha 1, neutrophil defensin 3, neutrophil defensin 4, defensin 5, defensin 6), β-defensins (e.g., beta-defensin 1, beta-defensin 2, beta-defensin 103, beta-defensin 107, beta-defensin 110, beta-defensin 136), and θ-defensins. In other embodiments, the anti-microbial polypeptide comprises or consists of a cathelicidin (e.g., hCAP18).

Anti-Viral Polypeptides

Anti-viral polypeptides (AVPs) are small peptides of variable length, sequence and structure with broad spectrum activity against a wide range of viruses. See, e.g., Zaiou, J Mol Med, 2007; 85:317. It has been shown that AVPs have a broad-spectrum of rapid onset of killing activities, with potentially low levels of induced resistance and concomitant broad anti-inflammatory effects. In some embodiments, the anti-viral polypeptide is under 10 kDa, e.g., under 8 kDa, 6 kDa, 4 kDa, 2 kDa, or lkDa. In some embodiments, the anti-viral polypeptide comprises or consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, about 25 to about 100 amino acids, about 50 to about 100 amino acids, or about 75 to about 100 amino acids. In certain embodiments, the anti-viral polypeptide comprises or consists of from about 15 to about 45 amino acids. In some embodiments, the anti-viral polypeptide is substantially cationic. In some embodiments, the anti-viral polypeptide is substantially amphipathic. In certain embodiments, the anti-viral polypeptide is substantially cationic and amphipathic. In some embodiments, the anti-viral polypeptide is cytostatic to a virus. In some embodiments, the anti-viral polypeptide is cytotoxic to a virus. In some embodiments, the anti-viral polypeptide is cytostatic and cytotoxic to a virus. In some embodiments, the anti-viral polypeptide is cytostatic to a bacterium, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-viral polypeptide is cytotoxic to a bacterium, fungus, protozoan, parasite, prion or a combination thereof. In certain embodiments, the anti-viral polypeptide is cytostatic and cytotoxic to a bacterium, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-viral polypeptide is cytotoxic to a tumor or cancer cell (e.g., a human cancer cell). In some embodiments, the anti-viral polypeptide is cytostatic to a tumor or cancer cell (e.g., a human cancer cell). In certain embodiments, the anti-viral polypeptide is cytotoxic and cytostatic to a tumor or cancer cell (e.g., a human cancer cell). In some embodiments, the anti-viral polypeptide is a secreted polypeptide.

Cytotoxic Nucleosides

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may incorporate one or more cytotoxic nucleosides. For example, cytotoxic nucleosides may be incorporated into polynucleotides such as bifunctional modified RNAs or mRNAs. Cytotoxic nucleoside anti-cancer agents include, but are not limited to, adenosine arabinoside, cytarabine, cytosine arabinoside, 5-fluorouracil, fludarabine, floxuridine, FTORAFUR® (a combination of tegafur and uracil), tegafur ((RS)-5-fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione), and 6-mercaptopurine.

A number of cytotoxic nucleoside analogues are in clinical use, or have been the subject of clinical trials, as anticancer agents. Examples of such analogues include, but are not limited to, cytarabine, gemcitabine, troxacitabine, decitabine, tezacitabine, 2′-deoxy-2′-methylidenecytidine (DMDC), cladribine, clofarabine, 5-azacytidine, 4′-thio-aracytidine, cyclopentenylcytosine and 1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-cytosine. Another example of such a compound is fludarabine phosphate. These compounds may be administered systemically and may have side effects which are typical of cytotoxic agents such as, but not limited to, little or no specificity for tumor cells over proliferating normal cells.

A number of prodrugs of cytotoxic nucleoside analogues are also reported in the art. Examples include, but are not limited to, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, N4-octadecyl-1-beta-D-arabinofuranosylcytosine, N4-palmitoyl-1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine, and P-4055 (cytarabine 5′-elaidic acid ester). In general, these prodrugs may be converted into the active drugs mainly in the liver and systemic circulation and display little or no selective release of active drug in the tumor tissue. For example, capecitabine, a prodrug of 5′-deoxy-5-fluorocytidine (and eventually of 5-fluorouracil), is metabolized both in the liver and in the tumor tissue. A series of capecitabine analogues containing “an easily hydrolysable radical under physiological conditions” has been claimed by Fujiu et al. (U.S. Pat. No. 4,966,891) and is herein incorporated by reference. The series described by Fujiu includes N4 alkyl and aralkyl carbamates of 5′-deoxy-5-fluorocytidine and the implication that these compounds will be activated by hydrolysis under normal physiological conditions to provide 5′-deoxy-5-fluorocytidine.

A series of cytarabine N4-carbamates has been by reported by Fadl et al (Pharmazie. 1995, 50, 382-7, herein incorporated by reference in its entirety) in which compounds were designed to convert into cytarabine in the liver and plasma. WO 2004/041203, herein incorporated by reference in its entirety, discloses prodrugs of gemcitabine, where some of the prodrugs are N4-carbamates. These compounds were designed to overcome the gastrointestinal toxicity of gemcitabine and were intended to provide gemcitabine by hydrolytic release in the liver and plasma after absorption of the intact prodrug from the gastrointestinal tract. Nomura et al (Bioorg Med. Chem. 2003, 11, 2453-61, herein incorporated by reference in its entirety) have described acetal derivatives of 1-(3-C-ethynyl-β-D-ribo-pentofaranosyl) cytosine which, on bioreduction, produced an intermediate that required further hydrolysis under acidic conditions to produce a cytotoxic nucleoside compound.

Cytotoxic nucleotides which may be chemotherapeutic also include, but are not limited to, pyrazolo [3,4-D]-pyrimidines, allopurinol, azathioprine, capecitabine, cytosine arabinoside, fluorouracil, mercaptopurine, 6-thioguanine, acyclovir, ara-adenosine, ribavirin, 7-deaza-adeno sine, 7-deaza-guanosine, 6-aza-uracil, 6-aza-cytidine, thymidine ribonucleotide, 5-bromodeoxyuridine, 2-chloro-purine, and inosine, or combinations thereof.

Polynucleotides Having Untranslated Regions (UTRs)

The polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may comprise one or more regions or parts which act or function as an untranslated region. Where polynucleotides are designed to encode at least one polypeptide of interest, the polynucleotides may comprise one or more of these untranslated regions.

By definition, wild type untranslated regions (UTRs) of a gene are transcribed but not translated. In mRNA, the 5′UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3′UTR starts immediately following the stop codon and continues until the transcriptional termination signal. There is growing body of evidence about the regulatory roles played by the UTRs in terms of stability of the nucleic acid molecule and translation. The regulatory features of a UTR can be incorporated into the polynucleotides of the present invention to, among other things, enhance the stability of the molecule. The specific features can also be incorporated to ensure controlled down-regulation of the transcript in case they are misdirected to undesired organs sites.

Tables 19 and 20 provide a listing of exemplary UTRs which may be utilized in the polynucleotides of the present invention. Shown in Table 19 is a listing of a 5′-untranslated region of the invention. Variants of 5′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.

TABLE 19 5′-Untranslated Regions 5′ UTR Name/ SEQ ID Identifier Description Sequence NO. 5UTR-001 Upstream UTR GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG 897 AAATATAAGAGCCACC 5UTR-002 Upstream UTR GGGAGATCAGAGAGAAAAGAAGAGTAAGAAG 898 AAATATAAGAGCCACC 5UTR-003 Upstream UTR GGAATAAAAGTCTCAACACAACATATACAAAA 899 CAAACGAATCTCAAGCAATCAAGCATTCTACT TCTATTGCAGCAATTTAAATCATTTCTTTTAAA GCAAAAGCAATTTTCTGAAAATTTTCACCATTT ACGAACGATAGCAAC 5UTR-004 Upstream UTR GGGAGACAAGCUUGGCAUUCCGGUACUGUUG 900 GUAAAGCCACC 5UTR-005 Upstream UTR GGGAGATCAGAGAGAAAAGAAGAGTAAGAAG 901 AAATATAAGAGCCACC 5UTR-006 Upstream UTR GGAATAAAAGTCTCAACACAACATATACAAAA 902 CAAACGAATCTCAAGCAATCAAGCATTCTACT TCTATTGCAGCAATTTAAATCATTTCTTTTAAA GCAAAAGCAATTTTCTGAAAATTTTCACCATTT ACGAACGATAGCAAC 5UTR-007 Upstream UTR GGGAGACAAGCUUGGCAUUCCGGUACUGUUG 903 GUAAAGCCACC 5UTR-008 Upstream UTR GGGAATTAACAGAGAAAAGAAGAGTAAGAAG 904 AAATATAAGAGCCACC 5UTR-009 Upstream UTR GGGAAATTAGACAGAAAAGAAGAGTAAGAAG 905 AAATATAAGAGCCACC 5UTR-010 Upstream UTR GGGAAATAAGAGAGTAAAGAACAGTAAGAAG 906 AAATATAAGAGCCACC 5UTR-011 Upstream UTR GGGAAAAAAGAGAGAAAAGAAGACTAAGAAG 907 AAATATAAGAGCCACC 5UTR-012 Upstream UTR GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG 908 ATATATAAGAGCCACC 5UTR-013 Upstream UTR GGGAAATAAGAGACAAAACAAGAGTAAGAAG 909 AAATATAAGAGCCACC 5UTR-014 Upstream UTR GGGAAATTAGAGAGTAAAGAACAGTAAGTAG 910 AATTAAAAGAGCCACC 5UTR-015 Upstream UTR GGGAAATAAGAGAGAATAGAAGAGTAAGAAG 911 AAATATAAGAGCCACC 5UTR-016 Upstream UTR GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG 912 AAAATTAAGAGCCACC 5UTR-017 Upstream UTR GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG 913 AAATTTAAGAGCCACC

Shown in Table 20 is a listing of 3′-untranslated regions of the invention. Variants of 3′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.

TABLE 20 3′-Untranslated Regions 3′ UTR Name/ SEQ ID Identifier Description Sequence NO. 3UTR-001 Creatine GCGCCTGCCCACCTGCCACCGACTGCTGGAACCCAGC 914 Kinase CAGTGGGAGGGCCTGGCCCACCAGAGTCCTGCTCCCT CACTCCTCGCCCCGCCCCCTGTCCCAGAGTCCCACCTG GGGGCTCTCTCCACCCTTCTCAGAGTTCCAGTTTCAAC CAGAGTTCCAACCAATGGGCTCCATCCTCTGGATTCTG GCCAATGAAATATCTCCCTGGCAGGGTCCTCTTCTTTT CCCAGAGCTCCACCCCAACCAGGAGCTCTAGTTAATG GAGAGCTCCCAGCACACTCGGAGCTTGTGCTTTGTCTC CACGCAAAGCGATAAATAAAAGCATTGGTGGCCTTTG GTCTTTGAATAAAGCCTGAGTAGGAAGTCTAGA 3UTR-002 Myoglobin GCCCCTGCCGCTCCCACCCCCACCCATCTGGGCCCCGG 915 GTTCAAGAGAGAGCGGGGTCTGATCTCGTGTAGCCAT ATAGAGTTTGCTTCTGAGTGTCTGCTTTGTTTAGTAGA GGTGGGCAGGAGGAGCTGAGGGGCTGGGGCTGGGGT GTTGAAGTTGGCTTTGCATGCCCAGCGATGCGCCTCCC TGTGGGATGTCATCACCCTGGGAACCGGGAGTGGCCC TTGGCTCACTGTGTTCTGCATGGTTTGGATCTGAATTA ATTGTCCTTTCTTCTAAATCCCAACCGAACTTCTTCCA ACCTCCAAACTGGCTGTAACCCCAAATCCAAGCCATT AACTACACCTGACAGTAGCAATTGTCTGATTAATCACT GGCCCCTTGAAGACAGCAGAATGTCCCTTTGCAATGA GGAGGAGATCTGGGCTGGGCGGGCCAGCTGGGGAAG CATTTGACTATCTGGAACTTGTGTGTGCCTCCTCAGGT ATGGCAGTGACTCACCTGGTTTTAATAAAACAACCTG CAACATCTCATGGTCTTTGAATAAAGCCTGAGTAGGA AGTCTAGA 3UTR-003 α-actin ACACACTCCACCTCCAGCACGCGACTTCTCAGGACGA 916 CGAATCTTCTCAATGGGGGGGCGGCTGAGCTCCAGCC ACCCCGCAGTCACTTTCTTTGTAACAACTTCCGTTGCT GCCATCGTAAACTGACACAGTGTTTATAACGTGTACAT ACATTAACTTATTACCTCATTTTGTTATTTTTCGAAACA AAGCCCTGTGGAAGAAAATGGAAAACTTGAAGAAGC ATTAAAGTCATTCTGTTAAGCTGCGTAAATGGTCTTTG AATAAAGCCTGAGTAGGAAGTCTAGA 3UTR-004 Albumin CATCACATTTAAAAGCATCTCAGCCTACCATGAGAAT 917 AAGAGAAAGAAAATGAAGATCAAAAGCTTATTCATCT GTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCT AAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCT CTGTGCTTCAATTAATAAAAAATGGAAAGAATCTAAT AGAGTGGTACAGCACTGTTATTTTTCAAAGATGTGTTG CTATCCTGAAAATTCTGTAGGTTCTGTGGAAGTTCCAG TGTTCTCTCTTATTCCACTTCGGTAGAGGATTTCTAGTT TCTTGTGGGCTAATTAAATAAATCATTAATACTCTTCT AATGGTCTTTGAATAAAGCCTGAGTAGGAAGTCTAGA 3UTR-005 α-globin GCTGCCTTCTGCGGGGCTTGCCTTCTGGCCATGCCCTT 918 CTTCTCTCCCTTGCACCTGTACCTCTTGGTCTTTGAATA AAGCCTGAGTAGGAAGGCGGCCGCTCGAGCATGCATC TAGA 3UTR-006 G-CSF GCCAAGCCCTCCCCATCCCATGTATTTATCTCTATTTA 919 ATATTTATGTCTATTTAAGCCTCATATTTAAAGACAGG GAAGAGCAGAACGGAGCCCCAGGCCTCTGTGTCCTTC CCTGCATTTCTGAGTTTCATTCTCCTGCCTGTAGCAGT GAGAAAAAGCTCCTGTCCTCCCATCCCCTGGACTGGG AGGTAGATAGGTAAATACCAAGTATTTATTACTATGA CTGCTCCCCAGCCCTGGCTCTGCAATGGGCACTGGGAT GAGCCGCTGTGAGCCCCTGGTCCTGAGGGTCCCCACC TGGGACCCTTGAGAGTATCAGGTCTCCCACGTGGGAG ACAAGAAATCCCTGTTTAATATTTAAACAGCAGTGTTC CCCATCTGGGTCCTTGCACCCCTCACTCTGGCCTCAGC CGACTGCACAGCGGCCCCTGCATCCCCTTGGCTGTGA GGCCCCTGGACAAGCAGAGGTGGCCAGAGCTGGGAG GCATGGCCCTGGGGTCCCACGAATTTGCTGGGGAATC TCGTTTTTCTTCTTAAGACTTTTGGGACATGGTTTGACT CCCGAACATCACCGACGCGTCTCCTGTTTTTCTGGGTG GCCTCGGGACACCTGCCCTGCCCCCACGAGGGTCAGG ACTGTGACTCTTTTTAGGGCCAGGCAGGTGCCTGGAC ATTTGCCTTGCTGGACGGGGACTGGGGATGTGGGAGG GAGCAGACAGGAGGAATCATGTCAGGCCTGTGTGTGA AAGGAAGCTCCACTGTCACCCTCCACCTCTTCACCCCC CACTCACCAGTGTCCCCTCCACTGTCACATTGTAACTG AACTTCAGGATAATAAAGTGTTTGCCTCCATGGTCTTT GAATAAAGCCTGAGTAGGAAGGCGGCCGCTCGAGCAT GCATCTAGA 3UTR-007 Col1a2; ACTCAATCTAAATTAAAAAAGAAAGAAATTTGAAAAA 920 collagen, ACTTTCTCTTTGCCATTTCTTCTTCTTCTTTTTTAACTGA type I, AAGCTGAATCCTTCCATTTCTTCTGCACATCTACTTGC alpha 2 TTAAATTGTGGGCAAAAGAGAAAAAGAAGGATTGATC AGAGCATTGTGCAATACAGTTTCATTAACTCCTTCCCC CGCTCCCCCAAAAATTTGAATTTTTTTTTCAACACTCTT ACACCTGTTATGGAAAATGTCAACCTTTGTAAGAAAA CCAAAATAAAAATTGAAAAATAAAAACCATAAACATT TGCACCACTTGTGGCTTTTGAATATCTTCCACAGAGGG AAGTTTAAAACCCAAACTTCCAAAGGTTTAAACTACC TCAAAACACTTTCCCATGAGTGTGATCCACATTGTTAG GTGCTGACCTAGACAGAGATGAACTGAGGTCCTTGTT TTGTTTTGTTCATAATACAAAGGTGCTAATTAATAGTA TTTCAGATACTTGAAGAATGTTGATGGTGCTAGAAGA ATTTGAGAAGAAATACTCCTGTATTGAGTTGTATCGTG TGGTGTATTTTTTAAAAAATTTGATTTAGCATTCATAT TTTCCATCTTATTCCCAATTAAAAGTATGCAGATTATT TGCCCAAATCTTCTTCAGATTCAGCATTTGTTCTTTGCC AGTCTCATTTTCATCTTCTTCCATGGTTCCACAGAAGC TTTGTTTCTTGGGCAAGCAGAAAAATTAAATTGTACCT ATTTTGTATATGTGAGATGTTTAAATAAATTGTGAAAA AAATGAAATAAAGCATGTTTGGTTTTCCAAAAGAACA TAT 3UTR-008 Col6a2; CGCCGCCGCCCGGGCCCCGCAGTCGAGGGTCGTGAGC 921 collagen, CCACCCCGTCCATGGTGCTAAGCGGGCCCGGGTCCCA type VI, CACGGCCAGCACCGCTGCTCACTCGGACGACGCCCTG alpha 2 GGCCTGCACCTCTCCAGCTCCTCCCACGGGGTCCCCGT AGCCCCGGCCCCCGCCCAGCCCCAGGTCTCCCCAGGC CCTCCGCAGGCTGCCCGGCCTCCCTCCCCCTGCAGCCA TCCCAAGGCTCCTGACCTACCTGGCCCCTGAGCTCTGG AGCAAGCCCTGACCCAATAAAGGCTTTGAACCCAT 3UTR-009 RPN1; GGGGCTAGAGCCCTCTCCGCACAGCGTGGAGACGGGG 922 ribophorin I CAAGGAGGGGGGTTATTAGGATTGGTGGTTTTGTTTTG CTTTGTTTAAAGCCGTGGGAAAATGGCACAACTTTACC TCTGTGGGAGATGCAACACTGAGAGCCAAGGGGTGGG AGTTGGGATAATTTTTATATAAAAGAAGTTTTTCCACT TTGAATTGCTAAAAGTGGCATTTTTCCTATGTGCAGTC ACTCCTCTCATTTCTAAAATAGGGACGTGGCCAGGCA CGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG CCGAGGCAGGCGGCTCACGAGGTCAGGAGATCGAGA CTATCCTGGCTAACACGGTAAAACCCTGTCTCTACTAA AAGTACAAAAAATTAGCTGGGCGTGGTGGTGGGCACC TGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAA AGGCATGAATCCAAGAGGCAGAGCTTGCAGTGAGCTG AGATCACGCCATTGCACTCCAGCCTGGGCAACAGTGT TAAGACTCTGTCTCAAATATAAATAAATAAATAAATA AATAAATAAATAAATAAAAATAAAGCGAGATGTTGCC CTCAAA 3UTR-010 LRP1; low GGCCCTGCCCCGTCGGACTGCCCCCAGAAAGCCTCCT 923 density GCCCCCTGCCAGTGAAGTCCTTCAGTGAGCCCCTCCCC lipoprotein AGCCAGCCCTTCCCTGGCCCCGCCGGATGTATAAATGT receptor- AAAAATGAAGGAATTACATTTTATATGTGAGCGAGCA related AGCCGGCAAGCGAGCACAGTATTATTTCTCCATCCCCT protein 1 CCCTGCCTGCTCCTTGGCACCCCCATGCTGCCTTCAGG GAGACAGGCAGGGAGGGCTTGGGGCTGCACCTCCTAC CCTCCCACCAGAACGCACCCCACTGGGAGAGCTGGTG GTGCAGCCTTCCCCTCCCTGTATAAGACACTTTGCCAA GGCTCTCCCCTCTCGCCCCATCCCTGCTTGCCCGCTCC CACAGCTTCCTGAGGGCTAATTCTGGGAAGGGAGAGT TCTTTGCTGCCCCTGTCTGGAAGACGTGGCTCTGGGTG AGGTAGGCGGGAAAGGATGGAGTGTTTTAGTTCTTGG GGGAGGCCACCCCAAACCCCAGCCCCAACTCCAGGGG CACCTATGAGATGGCCATGCTCAACCCCCCTCCCAGA CAGGCCCTCCCTGTCTCCAGGGCCCCCACCGAGGTTCC CAGGGCTGGAGACTTCCTCTGGTAAACATTCCTCCAGC CTCCCCTCCCCTGGGGACGCCAAGGAGGTGGGCCACA CCCAGGAAGGGAAAGCGGGCAGCCCCGTTTTGGGGAC GTGAACGTTTTAATAATTTTTGCTGAATTCCTTTACAA CTAAATAACACAGATATTGTTATAAATAAAATTGT 3UTR-011 Nnt1; ATATTAAGGATCAAGCTGTTAGCTAATAATGCCACCTC 924 cardio- TGCAGTTTTGGGAACAGGCAAATAAAGTATCAGTATA trophin-like CATGGTGATGTACATCTGTAGCAAAGCTCTTGGAGAA cytokine AATGAAGACTGAAGAAAGCAAAGCAAAAACTGTATA factor 1 GAGAGATTTTTCAAAAGCAGTAATCCCTCAATTTTAAA AAAGGATTGAAAATTCTAAATGTCTTTCTGTGCATATT TTTTGTGTTAGGAATCAAAAGTATTTTATAAAAGGAG AAAGAACAGCCTCATTTTAGATGTAGTCCTGTTGGATT TTTTATGCCTCCTCAGTAACCAGAAATGTTTTAAAAAA CTAAGTGTTTAGGATTTCAAGACAACATTATACATGGC TCTGAAATATCTGACACAATGTAAACATTGCAGGCAC CTGCATTTTATGTTTTTTTTTTCAACAAATGTGACTAAT TTGAAACTTTTATGAACTTCTGAGCTGTCCCCTTGCAA TTCAACCGCAGTTTGAATTAATCATATCAAATCAGTTT TAATTTTTTAAATTGTACTTCAGAGTCTATATTTCAAG GGCACATTTTCTCACTACTATTTTAATACATTAAAGGA CTAAATAATCTTTCAGAGATGCTGGAAACAAATCATTT GCTTTATATGTTTCATTAGAATACCAATGAAACATACA ACTTGAAAATTAGTAATAGTATTTTTGAAGATCCCATT TCTAATTGGAGATCTCTTTAATTTCGATCAACTTATAA TGTGTAGTACTATATTAAGTGCACTTGAGTGGAATTCA ACATTTGACTAATAAAATGAGTTCATCATGTTGGCAA GTGATGTGGCAATTATCTCTGGTGACAAAAGAGTAAA ATCAAATATTTCTGCCTGTTACAAATATCAAGGAAGA CCTGCTACTATGAAATAGATGACATTAATCTGTCTTCA CTGTTTATAATACGGATGGATTTTTTTTCAAATCAGTG TGTGTTTTGAGGTCTTATGTAATTGATGACATTTGAGA GAAATGGTGGCTTTTTTTAGCTACCTCTTTGTTCATTTA AGCACCAGTAAAGATCATGTCTTTTTATAGAAGTGTA GATTTTCTTTGTGACTTTGCTATCGTGCCTAAAGCTCT AAATATAGGTGAATGTGTGATGAATACTCAGATTATTT GTCTCTCTATATAATTAGTTTGGTACTAAGTTTCTCAA AAAATTATTAACACATGAAAGACAATCTCTAAACCAG AAAAAGAAGTAGTACAAATTTTGTTACTGTAATGCTC GCGTTTAGTGAGTTTAAAACACACAGTATCTTTTGGTT TTATAATCAGTTTCTATTTTGCTGTGCCTGAGATTAAG ATCTGTGTATGTGTGTGTGTGTGTGTGTGCGTTTGTGT GTTAAAGCAGAAAAGACTTTTTTAAAAGTTTTAAGTG ATAAATGCAATTTGTTAATTGATCTTAGATCACTAGTA AACTCAGGGCTGAATTATACCATGTATATTCTATTAGA AGAAAGTAAACACCATCTTTATTCCTGCCCTTTTTCTT CTCTCAAAGTAGTTGTAGTTATATCTAGAAAGAAGCA ATTTTGATTTCTTGAAAAGGTAGTTCCTGCACTCAGTT TAAACTAAAAATAATCATACTTGGATTTTATTTATTTT TGTCATAGTAAAAATTTTAATTTATATATATTTTTATTT AGTATTATCTTATTCTTTGCTATTTGCCAATCCTTTGTC ATCAATTGTGTTAAATGAATTGAAAATTCATGCCCTGT TCATTTTATTTTACTTTATTGGTTAGGATATTTAAAGG ATTTTTGTATATATAATTTCTTAAATTAATATTCCAAA AGGTTAGTGGACTTAGATTATAAATTATGGCAAAAAT CTAAAAACAACAAAAATGATTTTTATACATTCTATTTC ATTATTCCTCTTTTTCCAATAAGTCATACAATTGGTAG ATATGACTTATTTTATTTTTGTATTATTCACTATATCTT TATGATATTTAAGTATAAATAATTAAAAAAATTTATTG TACCTTATAGTCTGTCACCAAAAAAAAAAAATTATCT GTAGGTAGTGAAATGCTAATGTTGATTTGTCTTTAAGG GCTTGTTAACTATCCTTTATTTTCTCATTTGTCTTAAAT TAGGAGTTTGTGTTTAAATTACTCATCTAAGCAAAAAA TGTATATAAATCCCATTACTGGGTATATACCCAAAGG ATTATAAATCATGCTGCTATAAAGACACATGCACACG TATGTTTATTGCAGCACTATTCACAATAGCAAAGACTT GGAACCAACCCAAATGTCCATCAATGATAGACTTGAT TAAGAAAATGTGCACATATACACCATGGAATACTATG CAGCCATAAAAAAGGATGAGTTCATGTCCTTTGTAGG GACATGGATAAAGCTGGAAACCATCATTCTGAGCAAA CTATTGCAAGGACAGAAAACCAAACACTGCATGTTCT CACTCATAGGTGGGAATTGAACAATGAGAACACTTGG ACACAAGGTGGGGAACACCACACACCAGGGCCTGTCA TGGGGTGGGGGGAGTGGGGAGGGATAGCATTAGGAG ATATACCTAATGTAAATGATGAGTTAATGGGTGCAGC ACACCAACATGGCACATGTATACATATGTAGCAAACC TGCACGTTGTGCACATGTACCCTAGAACTTAAAGTATA ATTAAAAAAAAAAAGAAAACAGAAGCTATTTATAAA GAAGTTATTTGCTGAAATAAATGTGATCTTTCCCATTA AAAAAATAAAGAAATTTTGGGGTAAAAAAACACAAT ATATTGTATTCTTGAAAAATTCTAAGAGAGTGGATGTG AAGTGTTCTCACCACAAAAGTGATAACTAATTGAGGT AATGCACATATTAATTAGAAAGATTTTGTCATTCCACA ATGTATATATACTTAAAAATATGTTATACACAATAAAT ACATACATTAAAAAATAAGTAAATGTA 3UTR-012 Col6a1; CCCACCCTGCACGCCGGCACCAAACCCTGTCCTCCCAC 925 collagen, CCCTCCCCACTCATCACTAAACAGAGTAAAATGTGAT type VI, GCGAATTTTCCCGACCAACCTGATTCGCTAGATTTTTT alpha 1 TTAAGGAAAAGCTTGGAAAGCCAGGACACAACGCTGC TGCCTGCTTTGTGCAGGGTCCTCCGGGGCTCAGCCCTG AGTTGGCATCACCTGCGCAGGGCCCTCTGGGGCTCAG CCCTGAGCTAGTGTCACCTGCACAGGGCCCTCTGAGG CTCAGCCCTGAGCTGGCGTCACCTGTGCAGGGCCCTCT GGGGCTCAGCCCTGAGCTGGCCTCACCTGGGTTCCCC ACCCCGGGCTCTCCTGCCCTGCCCTCCTGCCCGCCCTC CCTCCTGCCTGCGCAGCTCCTTCCCTAGGCACCTCTGT GCTGCATCCCACCAGCCTGAGCAAGACGCCCTCTCGG GGCCTGTGCCGCACTAGCCTCCCTCTCCTCTGTCCCCA TAGCTGGTTTTTCCCACCAATCCTCACCTAACAGTTAC TTTACAATTAAACTCAAAGCAAGCTCTTCTCCTCAGCT TGGGGCAGCCATTGGCCTCTGTCTCGTTTTGGGAAACC AAGGTCAGGAGGCCGTTGCAGACATAAATCTCGGCGA CTCGGCCCCGTCTCCTGAGGGTCCTGCTGGTGACCGGC CTGGACCTTGGCCCTACAGCCCTGGAGGCCGCTGCTG ACCAGCACTGACCCCGACCTCAGAGAGTACTCGCAGG GGCGCTGGCTGCACTCAAGACCCTCGAGATTAACGGT GCTAACCCCGTCTGCTCCTCCCTCCCGCAGAGACTGGG GCCTGGACTGGACATGAGAGCCCCTTGGTGCCACAGA GGGCTGTGTCTTACTAGAAACAACGCAAACCTCTCCTT CCTCAGAATAGTGATGTGTTCGACGTTTTATCAAAGGC CCCCTTTCTATGTTCATGTTAGTTTTGCTCCTTCTGTGT TTTTTTCTGAACCATATCCATGTTGCTGACTTTTCCAAA TAAAGGTTTTCACTCCTCTC 3UTR-013 Calr; AGAGGCCTGCCTCCAGGGCTGGACTGAGGCCTGAGCG 926 calreticulin CTCCTGCCGCAGAGCTGGCCGCGCCAAATAATGTCTCT GTGAGACTCGAGAACTTTCATTTTTTTCCAGGCTGGTT CGGATTTGGGGTGGATTTTGGTTTTGTTCCCCTCCTCC ACTCTCCCCCACCCCCTCCCCGCCCTTTTTTTTTTTTTT TTTTAAACTGGTATTTTATCTTTGATTCTCCTTCAGCCC TCACCCCTGGTTCTCATCTTTCTTGATCAACATCTTTTC TTGCCTCTGTCCCCTTCTCTCATCTCTTAGCTCCCCTCC AACCTGGGGGGCAGTGGTGTGGAGAAGCCACAGGCCT GAGATTTCATCTGCTCTCCTTCCTGGAGCCCAGAGGAG GGCAGCAGAAGGGGGTGGTGTCTCCAACCCCCCAGCA CTGAGGAAGAACGGGGCTCTTCTCATTTCACCCCTCCC TTTCTCCCCTGCCCCCAGGACTGGGCCACTTCTGGGTG GGGCAGTGGGTCCCAGATTGGCTCACACTGAGAATGT AAGAACTACAAACAAAATTTCTATTAAATTAAATTTTG TGTCTCC 3UTR-014 Col1a1; CTCCCTCCATCCCAACCTGGCTCCCTCCCACCCAACCA 927 collagen, ACTTTCCCCCCAACCCGGAAACAGACAAGCAACCCAA type I, ACTGAACCCCCTCAAAAGCCAAAAAATGGGAGACAAT alpha 1 TTCACATGGACTTTGGAAAATATTTTTTTCCTTTGCATT CATCTCTCAAACTTAGTTTTTATCTTTGACCAACCGAA CATGACCAAAAACCAAAAGTGCATTCAACCTTACCAA AAAAAAAAAAAAAAAAAGAATAAATAAATAACTTTTT AAAAAAGGAAGCTTGGTCCACTTGCTTGAAGACCCAT GCGGGGGTAAGTCCCTTTCTGCCCGTTGGGCTTATGAA ACCCCAATGCTGCCCTTTCTGCTCCTTTCTCCACACCC CCCTTGGGGCCTCCCCTCCACTCCTTCCCAAATCTGTC TCCCCAGAAGACACAGGAAACAATGTATTGTCTGCCC AGCAATCAAAGGCAATGCTCAAACACCCAAGTGGCCC CCACCCTCAGCCCGCTCCTGCCCGCCCAGCACCCCCAG GCCCTGGGGGACCTGGGGTTCTCAGACTGCCAAAGAA GCCTTGCCATCTGGCGCTCCCATGGCTCTTGCAACATC TCCCCTTCGTTTTTGAGGGGGTCATGCCGGGGGAGCCA CCAGCCCCTCACTGGGTTCGGAGGAGAGTCAGGAAGG GCCACGACAAAGCAGAAACATCGGATTTGGGGAACGC GTGTCAATCCCTTGTGCCGCAGGGCTGGGCGGGAGAG ACTGTTCTGTTCCTTGTGTAACTGTGTTGCTGAAAGAC TACCTCGTTCTTGTCTTGATGTGTCACCGGGGCAACTG CCTGGGGGCGGGGATGGGGGCAGGGTGGAAGCGGCT CCCCATTTTATACCAAAGGTGCTACATCTATGTGATGG GTGGGGTGGGGAGGGAATCACTGGTGCTATAGAAATT GAGATGCCCCCCCAGGCCAGCAAATGTTCCTTTTTGTT CAAAGTCTATTTTTATTCCTTGATATTTTTCTTTTTTTTT TTTTTTTTTTGTGGATGGGGACTTGTGAATTTTTCTAAA GGTGCTATTTAACATGGGAGGAGAGCGTGTGCGGCTC CAGCCCAGCCCGCTGCTCACTTTCCACCCTCTCTCCAC CTGCCTCTGGCTTCTCAGGCCTCTGCTCTCCGACCTCT CTCCTCTGAAACCCTCCTCCACAGCTGCAGCCCATCCT CCCGGCTCCCTCCTAGTCTGTCCTGCGTCCTCTGTCCC CGGGTTTCAGAGACAACTTCCCAAAGCACAAAGCAGT TTTTCCCCCTAGGGGTGGGAGGAAGCAAAAGACTCTG TACCTATTTTGTATGTGTATAATAATTTGAGATGTTTTT AATTATTTTGATTGCTGGAATAAAGCATGTGGAAATG ACCCAAACATAATCCGCAGTGGCCTCCTAATTTCCTTC TTTGGAGTTGGGGGAGGGGTAGACATGGGGAAGGGG CTTTGGGGTGATGGGCTTGCCTTCCATTCCTGCCCTTT CCCTCCCCACTATTCTCTTCTAGATCCCTCCATAACCC CACTCCCCTTTCTCTCACCCTTCTTATACCGCAAACCTT TCTACTTCCTCTTTCATTTTCTATTCTTGCAATTTCCTT GCACCTTTTCCAAATCCTCTTCTCCCCTGCAATACCAT ACAGGCAATCCACGTGCACAACACACACACACACTCT TCACATCTGGGGTTGTCCAAACCTCATACCCACTCCCC TTCAAGCCCATCCACTCTCCACCCCCTGGATGCCCTGC ACTTGGTGGCGGTGGGATGCTCATGGATACTGGGAGG GTGAGGGGAGTGGAACCCGTGAGGAGGACCTGGGGG CCTCTCCTTGAACTGACATGAAGGGTCATCTGGCCTCT GCTCCCTTCTCACCCACGCTGACCTCCTGCCGAAGGAG CAACGCAACAGGAGAGGGGTCTGCTGAGCCTGGCGAG GGTCTGGGAGGGACCAGGAGGAAGGCGTGCTCCCTGC TCGCTGTCCTGGCCCTGGGGGAGTGAGGGAGACAGAC ACCTGGGAGAGCTGTGGGGAAGGCACTCGCACCGTGC TCTTGGGAAGGAAGGAGACCTGGCCCTGCTCACCACG GACTGGGTGCCTCGACCTCCTGAATCCCCAGAACACA ACCCCCCTGGGCTGGGGTGGTCTGGGGAACCATCGTG CCCCCGCCTCCCGCCTACTCCTTTTTAAGCTT 3UTR-015 Plod1 TTGGCCAGGCCTGACCCTCTTGGACCTTTCTTCTTTGC 928 procollagen- CGACAACCACTGCCCAGCAGCCTCTGGGACCTCGGGG lysine, 2- TCCCAGGGAACCCAGTCCAGCCTCCTGGCTGTTGACTT oxoglutarate CCCATTGCTCTTGGAGCCACCAATCAAAGAGATTCAA 5- AGAGATTCCTGCAGGCCAGAGGCGGAACACACCTTTA dioxygenase TGGCTGGGGCTCTCCGTGGTGTTCTGGACCCAGCCCCT 1 GGAGACACCATTCACTTTTACTGCTTTGTAGTGACTCG TGCTCTCCAACCTGTCTTCCTGAAAAACCAAGGCCCCC TTCCCCCACCTCTTCCATGGGGTGAGACTTGAGCAGAA CAGGGGCTTCCCCAAGTTGCCCAGAAAGACTGTCTGG GTGAGAAGCCATGGCCAGAGCTTCTCCCAGGCACAGG TGTTGCACCAGGGACTTCTGCTTCAAGTTTTGGGGTAA AGACACCTGGATCAGACTCCAAGGGCTGCCCTGAGTC TGGGACTTCTGCCTCCATGGCTGGTCATGAGAGCAAA CCGTAGTCCCCTGGAGACAGCGACTCCAGAGAACCTC TTGGGAGACAGAAGAGGCATCTGTGCACAGCTCGATC TTCTACTTGCCTGTGGGGAGGGGAGTGACAGGTCCAC ACACCACACTGGGTCACCCTGTCCTGGATGCCTCTGAA GAGAGGGACAGACCGTCAGAAACTGGAGAGTTTCTAT TAAAGGTCATTTAAACCA 3UTR-016 Nucb1; TCCTCCGGGACCCCAGCCCTCAGGATTCCTGATGCTCC 929 nucleobindin AAGGCGACTGATGGGCGCTGGATGAAGTGGCACAGTC 1 AGCTTCCCTGGGGGCTGGTGTCATGTTGGGCTCCTGGG GCGGGGGCACGGCCTGGCATTTCACGCATTGCTGCCA CCCCAGGTCCACCTGTCTCCACTTTCACAGCCTCCAAG TCTGTGGCTCTTCCCTTCTGTCCTCCGAGGGGCTTGCC TTCTCTCGTGTCCAGTGAGGTGCTCAGTGATCGGCTTA ACTTAGAGAAGCCCGCCCCCTCCCCTTCTCCGTCTGTC CCAAGAGGGTCTGCTCTGAGCCTGCGTTCCTAGGTGG CTCGGCCTCAGCTGCCTGGGTTGTGGCCGCCCTAGCAT CCTGTATGCCCACAGCTACTGGAATCCCCGCTGCTGCT CCGGGCCAAGCTTCTGGTTGATTAATGAGGGCATGGG GTGGTCCCTCAAGACCTTCCCCTACCTTTTGTGGAACC AGTGATGCCTCAAAGACAGTGTCCCCTCCACAGCTGG GTGCCAGGGGCAGGGGATCCTCAGTATAGCCGGTGAA CCCTGATACCAGGAGCCTGGGCCTCCCTGAACCCCTG GCTTCCAGCCATCTCATCGCCAGCCTCCTCCTGGACCT CTTGGCCCCCAGCCCCTTCCCCACACAGCCCCAGAAG GGTCCCAGAGCTGACCCCACTCCAGGACCTAGGCCCA GCCCCTCAGCCTCATCTGGAGCCCCTGAAGACCAGTC CCACCCACCTTTCTGGCCTCATCTGACACTGCTCCGCA TCCTGCTGTGTGTCCTGTTCCATGTTCCGGTTCCATCCA AATACACTTTCTGGAACAAA 3UTR-017 α-globin GCTGGAGCCTCGGTGGCCATGCTTCTTGCCCCTTGGGC 930 CTCCCCCCAGCCCCTCCTCCCCTTCCTGCACCCGTACC CCCGTGGTCTTTGAATAAAGTCTGAGTGGGCGGC 5′ UTR and Translation Initiation

Natural 5′UTRs bear features which play roles in translation initiation. They harbor signatures like Kozak sequences which are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A/G)CCAUGG (SEQ ID NO: 965), where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’. 5′UTR also have been known to form secondary structures which are involved in elongation factor binding.

By engineering the features typically found in abundantly expressed genes of specific target organs, one can enhance the stability and protein production of the polynucleotides of the invention. For example, introduction of 5′ UTR of liver-expressed mRNA, such as albumin, serum amyloid A, Apolipoprotein A/B/E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII, could be used to enhance expression of a nucleic acid molecule, such as a polynucleotides, in hepatic cell lines or liver. Likewise, use of 5′ UTR from other tissue-specific mRNA to improve expression in that tissue is possible for muscle (MyoD, Myosin, Myoglobin, Myogenin, Herculin), for endothelial cells (Tie-1, CD36), for myeloid cells (C/EBP, AML1, G-CSF, GM-CSF, CD11b, MSR, Fr-1, i-NOS), for leukocytes (CD45, CD18), for adipose tissue (CD36, GLUT4, ACRP30, adiponectin) and for lung epithelial cells (SP-A/B/C/D).

Untranslated regions useful in the design and manufacture of polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) include, but are not limited, to those disclosed in co-pending, co-owned U.S. Provisional application Ser. No. 61/829,372, U.S. Provisional application Ser. No. 61/829,372, and International Application, PCT/US14/21522 filed Mar. 7, 2014, the contents of each of which are incorporated herein by reference in its entirety.

Other non-UTR sequences may also be used as regions or subregions within the polynucleotides. For example, introns or portions of introns sequences may be incorporated into regions of the polynucleotides of the invention. Incorporation of intronic sequences may increase protein production as well as polynucletoide levels.

Combinations of features may be included in flanking regions and may be contained within other features. For example, the ORF may be flanked by a 5′ UTR which may contain a strong Kozak translational initiation signal and/or a 3′ UTR which may include an oligo(dT) sequence for templated addition of a poly-A tail. 5′UTR may comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and/or different genes such as the 5′UTRs described in US Patent Application Publication No. 20100293625, herein incorporated by reference in its entirety.

Co-pending, co-owned U.S. Provisional U.S. application Ser. No. 61/829,372 and U.S. Provisional Application 61/829,372 (U.S. Ser. No.) provides a listing of exemplary UTRs which may be utilized in the polynucleotide of the present invention as flanking regions. Variants of 5′ or 3′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.

It should be understood that any UTR from any gene may be incorporated into the regions of the polynucleotide. Furthermore, multiple wild-type UTRs of any known gene may be utilized. It is also within the scope of the present invention to provide artificial UTRs which are not variants of wild type regions. These UTRs or portions thereof may be placed in the same orientation as in the transcript from which they were selected or may be altered in orientation or location. Hence a 5′ or 3′ UTR may be inverted, shortened, lengthened, made with one or more other 5′ UTRs or 3′ UTRs. As used herein, the term “altered” as it relates to a UTR sequence, means that the UTR has been changed in some way in relation to a reference sequence. For example, a 3′ or 5′ UTR may be altered relative to a wild type or native UTR by the change in orientation or location as taught above or may be altered by the inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. Any of these changes producing an “altered” UTR (whether 3′ or 5′) comprise a variant UTR.

In one embodiment, a double, triple or quadruple UTR such as a 5′ or 3′ UTR may be used. As used herein, a “double” UTR is one in which two copies of the same UTR are encoded either in series or substantially in series. For example, a double beta-globin 3′ UTR may be used as described in US Patent publication 20100129877, the contents of which are incorporated herein by reference in its entirety.

It is also within the scope of the present invention to have patterned UTRs. As used herein “patterned UTRs” are those UTRs which reflect a repeating or alternating pattern, such as ABABAB or AABBAABBAABB or ABCABCABC or variants thereof repeated once, twice, or more than 3 times. In these patterns, each letter, A, B, or C represent a different UTR at the nucleotide level.

In one embodiment, flanking regions are selected from a family of transcripts whose proteins share a common function, structure, feature of property. For example, polypeptides of interest may belong to a family of proteins which are expressed in a particular cell, tissue or at some time during development. The UTRs from any of these genes may be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide. As used herein, a “family of proteins” is used in the broadest sense to refer to a group of two or more polypeptides of interest which share at least one function, structure, feature, localization, origin, or expression pattern.

The untranslated region may also include translation enhancer elements (TEE). As a non-limiting example, the TEE may include those described in US Application No. 20090226470, herein incorporated by reference in its entirety, and those known in the art.

3′ UTR and the AU Rich Elements

Natural or wild type 3′ UTRs are known to have stretches of Adenosines and Uridines embedded in them. These AU rich signatures are particularly prevalent in genes with high rates of turnover. Based on their sequence features and functional properties, the AU rich elements (AREs) can be separated into three classes (Chen et al, 1995): Class I AREs contain several dispersed copies of an AUUUA motif within U-rich regions. C-Myc and MyoD contain class I AREs. Class II AREs possess two or more overlapping UUAUUUA(U/A)(U/A) nonamers. Molecules containing this type of AREs include GM-CSF and TNF-a. Class III ARES are less well defined. These U rich regions do not contain an AUUUA motif. c-Jun and Myogenin are two well-studied examples of this class. Most proteins binding to the AREs are known to destabilize the messenger, whereas members of the ELAV family, most notably HuR, have been documented to increase the stability of mRNA. HuR binds to AREs of all the three classes. Engineering the HuR specific binding sites into the 3′ UTR of nucleic acid molecules will lead to HuR binding and thus, stabilization of the message in vivo.

Introduction, removal or modification of 3′ UTR AU rich elements (AREs) can be used to modulate the stability of polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention). When engineering specific polynucleotides, one or more copies of an ARE can be introduced to make polynucleotides of the invention less stable and thereby curtail translation and decrease production of the resultant protein. Likewise, AREs can be identified and removed or mutated to increase the intracellular stability and thus increase translation and production of the resultant protein. Transfection experiments can be conducted in relevant cell lines, using polynucleotides of the invention and protein production can be assayed at various time points post-transfection. For example, cells can be transfected with different ARE-engineering molecules and by using an ELISA kit to the relevant protein and assaying protein produced at 6 hour, 12 hour, 24 hour, 48 hour, and 7 days post-transfection.

microRNA Binding Sites

microRNAs (or miRNA) are 19-25 nucleotide long noncoding RNAs that bind to the 3′UTR of nucleic acid molecules and down-regulate gene expression either by reducing nucleic acid molecule stability or by inhibiting translation. The polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may comprise one or more microRNA target sequences, microRNA seqences, or microRNA seeds. Such sequences may correspond to any known microRNA such as those taught in US Publication US2005/0261218 and US Publication US2005/0059005, the contents of which are incorporated herein by reference in their entirety.

A microRNA sequence comprises a “seed” region, i.e., a sequence in the region of positions 2-8 of the mature microRNA, which sequence has perfect Watson-Crick complementarity to the miRNA target sequence. A microRNA seed may comprise positions 2-8 or 2-7 of the mature microRNA. In some embodiments, a microRNA seed may comprise 7 nucleotides (e.g., nucleotides 2-8 of the mature microRNA), wherein the seed-complementary site in the corresponding miRNA target is flanked by an adenine (A) opposed to microRNA position 1. In some embodiments, a microRNA seed may comprise 6 nucleotides (e.g., nucleotides 2-7 of the mature microRNA), wherein the seed-complementary site in the corresponding miRNA target is flanked byan adenine (A) opposed to microRNA position 1. See for example, Grimson A, Farh K K, Johnston W K, Garrett-Engele P, Lim L P, Bartel D P; Mol Cell. 2007 July 6; 27(1):91-105; each of which is herein incorporated by reference in their entirety. The bases of the microRNA seed have complete complementarity with the target sequence. By engineering microRNA target sequences into the polynucleotides (e.g., in a 3′UTR like region or other region) of the invention one can target the molecule for degradation or reduced translation, provided the microRNA in question is available. This process will reduce the hazard of off target effects upon nucleic acid molecule delivery. Identification of microRNA, microRNA target regions, and their expression patterns and role in biology have been reported (Bonauer et al., Curr Drug Targets 2010 11:943-949; Anand and Cheresh Curr Opin Hematol 2011 18:171-176; Contreras and Rao Leukemia 2012 26:404-413 (2011 December 20. doi: 10.1038/leu.2011.356); Bartel Cell 2009 136:215-233; Landgraf et al, Cell, 2007 129:1401-1414; each of which is herein incorporated by reference in its entirety).

For example, if the nucleic acid molecule is an mRNA and is not intended to be delivered to the liver but ends up there, then miR-122, a microRNA abundant in liver, can inhibit the expression of the gene of interest if one or multiple target sites of miR-122 are engineered into the 3′ UTR region of the polynucleotides. Introduction of one or multiple binding sites for different microRNA can be engineered to further decrease the longevity, stability, and protein translation of polynucleotides.

As used herein, the term “microRNA site” refers to a microRNA target site or a microRNA recognition site, or any nucleotide sequence to which a microRNA binds or associates. It should be understood that “binding” may follow traditional Watson-Crick hybridization rules or may reflect any stable association of the microRNA with the target sequence at or adjacent to the microRNA site.

Conversely, for the purposes of the polynucleotides of the present invention, microRNA binding sites can be engineered out of (i.e. removed from) sequences in which they occur, e.g., in order to increase protein expression in specific tissues. For example, miR-122 binding sites may be removed to improve protein expression in the liver. Regulation of expression in multiple tissues can be accomplished through introduction or removal or one or several microRNA binding sites.

Examples of tissues where microRNA are known to regulate mRNA, and thereby protein expression, include, but are not limited to, liver (miR-122), muscle (miR-133, miR-206, miR-208), endothelial cells (miR-17-92, miR-126), myeloid cells (miR-142-3p, miR-142-5p, miR-16, miR-21, miR-223, miR-24, miR-27), adipose tissue (let-7, miR-30c), heart (miR-1d, miR-149), kidney (miR-192, miR-194, miR-204), and lung epithelial cells (let-7, miR-133, miR-126). MicroRNA can also regulate complex biological processes such as angiogenesis (miR-132) (Anand and Cheresh Curr Opin Hematol 2011 18:171-176; herein incorporated by reference in its entirety).

Expression profiles, microRNA and cell lines useful in the present invention include those taught in for example, U.S. Provisional Application Nos 61/857,436 and 61/857,304 each filed Jul. 23, 2013, the contents of which are incorporated by reference in their entirety.

In the polynucleotides of the present invention, binding sites for microRNAs that are involved in such processes may be removed or introduced, in order to tailor the expression of the polynucleotides expression to biologically relevant cell types or to the context of relevant biological processes. A listing of microRNA, miR sequences and miR binding sites is listed in Table 9 of U.S. Provisional Application No. 61/753,661 filed Jan. 17, 2013, in Table 9 of U.S. Provisional Application No. 61/754,159 filed Jan. 18, 2013, and in Table 7 of U.S. Provisional Application No. 61/758,921 filed Jan. 31, 2013, each of which are herein incorporated by reference in their entireties.

Examples of use of microRNA to drive tissue or disease-specific gene expression are listed (Getner and Naldini, Tissue Antigens. 2012, 80:393-403; herein incorporated by reference in its entirety). In addition, microRNA seed sites can be incorporated into mRNA to decrease expression in certain cells which results in a biological improvement. An example of this is incorporation of miR-142 sites into a UGT1A1-expressing lentiviral vector. The presence of miR-142 seed sites reduced expression in hematopoietic cells, and as a consequence reduced expression in antigen-presentating cells, leading to the absence of an immune response against the virally expressed UGT1A1 (Schmitt et al., Gastroenterology 2010; 139:999-1007; Gonzalez-Asequinolaza et al. Gastroenterology 2010, 139:726-729; both herein incorporated by reference in its entirety). Incorporation of miR-142 sites into modified mRNA could not only reduce expression of the encoded protein in hematopoietic cells, but could also reduce or abolish immune responses to the mRNA-encoded protein. Incorporation of miR-142 seed sites (one or multiple) into mRNA would be important in the case of treatment of patients with complete protein deficiencies (UGT1A1 type I, LDLR-deficient patients, CRIM-negative Pompe patients, etc.).

Lastly, through an understanding of the expression patterns of microRNA in different cell types, polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) can be engineered for more targeted expression in specific cell types or only under specific biological conditions. Through introduction of tissue-specific microRNA binding sites, polynucleotides could be designed that would be optimal for protein expression in a tissue or in the context of a biological condition.

Transfection experiments can be conducted in relevant cell lines, using engineered polynucleotides and protein production can be assayed at various time points post-transfection. For example, cells can be transfected with different microRNA binding site-engineering polynucleotides and by using an ELISA kit to the relevant protein and assaying protein produced at 6 hour, 12 hour, 24 hour, 48 hour, 72 hour and 7 days post-transfection. In vivo experiments can also be conducted using microRNA-binding site-engineered molecules to examine changes in tissue-specific expression of formulated polynucleotides.

Regions Having a 5′ Cap

The 5′ cap structure of a natural mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsibile for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5′ proximal introns removal during mRNA splicing.

Endogenous mRNA molecules may be 5′-end capped generating a 5′-ppp-5′-triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule. This 5′-guanylate cap may then be methylated to generate an N7-methyl-guanylate residue. The ribose sugars of the terminal and/or anteterminal transcribed nucleotides of the 5′ end of the mRNA may optionally also be 2′-O-methylated. 5′-decapping through hydrolysis and cleavage of the guanylate cap structure may target a nucleic acid molecule, such as an mRNA molecule, for degradation.

In some embodiments, polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be designed to incorporate a cap moiety. Modifications to the polynucleotides of the present invention may generate a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. Because cap structure hydrolysis requires cleavage of 5′-ppp-5′ phosphorodiester linkages, modified nucleotides may be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, Mass.) may be used with α-thio-guanosine nucleotides according to the manufacturer's instructions to create a phosphorothioate linkage in the 5′-ppp-5′ cap. Additional modified guanosine nucleotides may be used such as α-methyl-phosphonate and seleno-phosphate nucleotides.

Additional modifications include, but are not limited to, 2′-O-methylation of the ribose sugars of 5′-terminal and/or 5′-anteterminal nucleotides of the polynucleotide (as mentioned above) on the 2′-hydroxyl group of the sugar ring. Multiple distinct 5′-cap structures can be used to generate the 5′-cap of a nucleic acid molecule, such as a polynucleotide which functions as an mRNA molecule.

Cap analogs, which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e. endogenous, wild-type or physiological) 5′-caps in their chemical structure, while retaining cap function. Cap analogs may be chemically (i.e. non-enzymatically) or enzymatically synthesized and/or linked to the polynucleotides of the invention.

For example, the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5′-5′-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3′-O-methyl group (i.e., N7,3′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine (m⁷G-3′mppp-G; which may equivaliently be designated 3′ O-Me-m7G(5′)ppp(5′)G). The 3′-O atom of the other, unmodified, guanine becomes linked to the 5′-terminal nucleotide of the capped polynucleotide. The N7- and 3′-O-methlyated guanine provides the terminal moiety of the capped polynucleotide.

Another exemplary cap is mCAP, which is similar to ARCA but has a 2′-O-methyl group on guanosine (i.e., N7,2′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine, m⁷Gm-ppp-G).

In one embodiment, the cap is a dinucleotide cap analog. As a non-limiting example, the dinucleotide cap analog may be modified at different phosphate positions with a boranophosphate group or a phophoroselenoate group such as the dinucleotide cap analogs described in U.S. Pat. No. 8,519,110, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the cap is a cap analog is a N7-(4-chlorophenoxyethyl) substituted dicucleotide form of a cap analog known in the art and/or described herein. Non-limiting examples of a N7-(4-chlorophenoxyethyl) substituted dicucleotide form of a cap analog include a N7-(4-chlorophenoxyethyl)-G(5′)ppp(5′)G and a N7-(4-chlorophenoxyethyl)-m^(3′-O)G(5′)ppp(5′)G cap analog (See e.g., the various cap analogs and the methods of synthesizing cap analogs described in Kore et al. Bioorganic & Medicinal Chemistry 2013 21:4570-4574; the contents of which are herein incorporated by reference in its entirety). In another embodiment, a cap analog of the present invention is a 4-chloro/bromophenoxyethyl analog.

While cap analogs allow for the concomitant capping of a polynucleotide or a region thereof, in an in vitro transcription reaction, up to 20% of transcripts can remain uncapped. This, as well as the structural differences of a cap analog from an endogenous 5′-cap structures of nucleic acids produced by the endogenous, cellular transcription machinery, may lead to reduced translational competency and reduced cellular stability.

Polynucleotides of the invention may also be capped post-manufacture (whether IVT or chemical synthesis), using enzymes, in order to generate more authentic 5′-cap structures. As used herein, the phrase “more authentic” refers to a feature that closely mirrors or mimics, either structurally or functionally, an endogenous or wild type feature. That is, a “more authentic” feature is better representative of an endogenous, wild-type, natural or physiological cellular function and/or structure as compared to synthetic features or analogs, etc., of the prior art, or which outperforms the corresponding endogenous, wild-type, natural or physiological feature in one or more respects. Non-limiting examples of more authentic 5′cap structures of the present invention are those which, among other things, have enhanced binding of cap binding proteins, increased half life, reduced susceptibility to 5′ endonucleases and/or reduced 5′decapping, as compared to synthetic 5′cap structures known in the art (or to a wild-type, natural or physiological 5′cap structure). For example, recombinant Vaccinia Virus Capping Enzyme and recombinant 2′-O-methyltransferase enzyme can create a canonical 5′-5′-triphosphate linkage between the 5′-terminal nucleotide of a polynucleotide and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5′-terminal nucleotide of the mRNA contains a 2′-O-methyl. Such a structure is termed the Cap1 structure. This cap results in a higher translational-competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e.g., to other 5′cap analog structures known in the art. Cap structures include, but are not limited to, 7mG(5′)ppp(5′)N,pN2p (cap 0), 7mG(5′)ppp(5′)NlmpNp (cap 1), and 7mG(5′)-ppp(5′)NlmpN2mp (cap 2).

As a non-limiting example, capping chimeric polynucleotides post-manufacture may be more efficient as nearly 100% of the chimeric polynucleotides may be capped. This is in contrast to ˜80% when a cap analog is linked to a chimeric polynucleotide in the course of an in vitro transcription reaction.

According to the present invention, 5′ terminal caps may include endogenous caps or cap analogs. According to the present invention, a 5′ terminal cap may comprise a guanine analog. Useful guanine analogs include, but are not limited to, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine.

Viral Sequences

Additional viral sequences such as, but not limited to, the translation enhancer sequence of the barley yellow dwarf virus (BYDV-PAV), the Jaagsiekte sheep retrovirus (JSRV) and/or the Enzootic nasal tumor virus (See e.g., International Pub. No. WO2012129648; herein incorporated by reference in its entirety) can be engineered and inserted in the polynucleotides of the invention and can stimulate the translation of the construct in vitro and in vivo. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12 hr, 24 hr, 48 hr, 72 hr and day 7 post-transfection.

IRES Sequences

Further, provided are polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) which may contain an internal ribosome entry site (IRES). First identified as a feature Picorna virus RNA, IRES plays an important role in initiating protein synthesis in absence of the 5′ cap structure. An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA. Polynucleotides containing more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes (“multicistronic nucleic acid molecules”). When polynucleotides are provided with an IRES, further optionally provided is a second translatable region. Examples of IRES sequences that can be used according to the invention include without limitation, those from picornaviruses (e.g. FMDV), pest viruses (CFFV), polio viruses (PV), encephalomyocarditis viruses (ECMV), foot-and-mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV).

Poly-A Tails

During RNA processing, a long chain of adenine nucleotides (poly-A tail) may be added to a polynucleotide such as an mRNA molecule in order to increase stability. Immediately after transcription, the 3′ end of the transcript may be cleaved to free a 3′ hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 80 to approximately 250 residues long, including approximately 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 residues long.

PolyA tails may also be added after the construct is exported from the nucleus.

According to the present invention, terminal groups on the poly A tail may be incorporated for stabilization into polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the RNAVs of the invention). Polynucleotides of the present invention may incude des-3′ hydroxyl tails. They may also include structural moieties or 2′-Omethyl modifications as taught by Junjie Li, et al. (Current Biology, Vol. 15, 1501-1507, Aug. 23, 2005, the contents of which are incorporated herein by reference in its entirety).

The polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be desiged to encode transcripts with alternative polyA tail structures including histone mRNA. According to Norbury, “Terminal uridylation has also been detected on human replication-dependent histone mRNAs. The turnover of these mRNAs is thought to be important for the prevention of potentially toxic histone accumulation following the completion or inhibition of chromosomal DNA replication. These mRNAs are distinguished by their lack of a 3′ poly(A) tail, the function of which is instead assumed by a stable stem-loop structure and its cognate stem-loop binding protein (SLBP); the latter carries out the same functions as those of PABP on polyadenylated mRNAs” (Norbury, “Cytoplasmic RNA: a case of the tail wagging the dog,” Nature Reviews Molecular Cell Biology; AOP, published online 29 Aug. 2013; doi:10.1038/nrm3645) the contents of which are incorporated herein by reference in its entirety.

Unique poly-A tail lengths provide certain advantages to the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention).

Generally, the length of a poly-A tail, when present, is greater than 30 nucleotides in length. In another embodiment, the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides). In some embodiments, the polynucleotide or region thereof includes from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 2,000 to 3,000, from 2,000 to 2,500, and from 2,500 to 3,000).

In one embodiment, the poly-A tail is designed relative to the length of the overall polynucleotide or the length of a particular region of the polynucleotide. This design may be based on the length of a coding region, the length of a particular feature or region or based on the length of the ultimate product expressed from the polynucleotides.

In this context the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the polynucleotide or feature thereof. The poly-A tail may also be designed as a fraction of the polynucleotides to which it belongs. In this context, the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the total length of the construct, a construct region or the total length of the construct minus the poly-A tail. Further, engineered binding sites and conjugation of polynucleotides for Poly-A binding protein may enhance expression.

Additionally, multiple distinct polynucleotides may be linked together via the PABP (Poly-A binding protein) through the 3′-end using modified nucleotides at the 3′-terminus of the poly-A tail. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12 hr, 24 hr, 48 hr, 72 hr and day 7 post-transfection.

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) are designed to include a polyA-G Quartet region. The G-quartet is a cyclic hydrogen bonded array of four guanine nucleotides that can be formed by G-rich sequences in both DNA and RNA. In this embodiment, the G-quartet is incorporated at the end of the poly-A tail.

The resultant polynucleotide is assayed for stability, protein production and other parameters including half-life at various time points. It has been discovered that the polyA-G quartet results in protein production from an mRNA equivalent to at least 75% of that seen using a poly-A tail of 120 nucleotides alone.

Start Codon Region

In some embodiments, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may have regions that are analogous to or function like a start codon region.

In one embodiment, the translation of a polynucleotide may initiate on a codon which is not the start codon AUG. Translation of the polynucleotide may initiate on an alternative start codon such as, but not limited to, ACG, AGG, AAG, CTG/CUG, GTG/GUG, ATA/AUA, ATT/AUU, TTG/UUG (see Touriol et al. Biology of the Cell 95 (2003) 169-178 and Matsuda and Mauro PLoS ONE, 2010 5:11; the contents of each of which are herein incorporated by reference in its entirety). As a non-limiting example, the translation of a polynucleotide begins on the alternative start codon ACG. As another non-limiting example, polynucleotide translation begins on the alternative start codon CTG or CUG. As yet another non-limiting example, the translation of a polynucleotide begins on the alternative start codon GTG or GUG.

Nucleotides flanking a codon that initiates translation such as, but not limited to, a start codon or an alternative start codon, are known to affect the translation efficiency, the length and/or the structure of the polynucleotide. (See e.g., Matsuda and Mauro PLoS ONE, 2010 5:11; the contents of which are herein incorporated by reference in its entirety). Masking any of the nucleotides flanking a codon that initiates translation may be used to alter the position of translation initiation, translation efficiency, length and/or structure of a polynucleotide.

In one embodiment, a masking agent may be used near the start codon or alternative start codon in order to mask or hide the codon to reduce the probability of translation initiation at the masked start codon or alternative start codon. Non-limiting examples of masking agents include antisense locked nucleic acids (LNA) polynucleotides and exon-junction complexes (EJCs) (See e.g., Matsuda and Mauro describing masking agents LNA polynucleotides and EJCs (PLoS ONE, 2010 5:11); the contents of which are herein incorporated by reference in its entirety).

In another embodiment, a masking agent may be used to mask a start codon of a polynucleotide in order to increase the likelihood that translation will initiate on an alternative start codon.

In one embodiment, a masking agent may be used to mask a first start codon or alternative start codon in order to increase the chance that translation will initiate on a start codon or alternative start codon downstream to the masked start codon or alternative start codon.

In one embodiment, a start codon or alternative start codon may be located within a perfect complement for a miR binding site. The perfect complement of a miR binding site may help control the translation, length and/or structure of the polynucleotide similar to a masking agent. As a non-limiting example, the start codon or alternative start codon may be located in the middle of a perfect complement for a miR-122 binding site. The start codon or alternative start codon may be located after the first nucleotide, second nucleotide, third nucleotide, fourth nucleotide, fifth nucleotide, sixth nucleotide, seventh nucleotide, eighth nucleotide, ninth nucleotide, tenth nucleotide, eleventh nucleotide, twelfth nucleotide, thirteenth nucleotide, fourteenth nucleotide, fifteenth nucleotide, sixteenth nucleotide, seventeenth nucleotide, eighteenth nucleotide, nineteenth nucleotide, twentieth nucleotide or twenty-first nucleotide.

In another embodiment, the start codon of a polynucleotide may be removed from the polynucleotide sequence in order to have the translation of the polynucleotide begin on a codon which is not the start codon. Translation of the polynucleotide may begin on the codon following the removed start codon or on a downstream start codon or an alternative start codon. In a non-limiting example, the start codon ATG or AUG is removed as the first 3 nucleotides of the polynucleotide sequence in order to have translation initiate on a downstream start codon or alternative start codon. The polynucleotide sequence where the start codon was removed may further comprise at least one masking agent for the downstream start codon and/or alternative start codons in order to control or attempt to control the initiation of translation, the length of the polynucleotide and/or the structure of the polynucleotide.

Stop Codon Region

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may include at least two stop codons before the 3′ untranslated region (UTR). The stop codon may be selected from TGA, TAA and TAG. In one embodiment, the polynucleotides of the present invention include the stop codon TGA and one additional stop codon. In a further embodiment the addition stop codon may be TAA. In another embodiment, the polynucleotides of the present invention include three stop codons.

Signal Sequences

The polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may also encode additional features which facilitate trafficking of the polypeptides to therapeutically relevant sites. One such feature which aids in protein trafficking is the signal sequence. As used herein, a “signal sequence” or “signal peptide” is a polynucleotide or polypeptide, respectively, which is from about 9 to 200 nucleotides (3-60 amino acids) in length which is incorporated at the 5′ (or N-terminus) of the coding region or polypeptide encoded, respectively. Addition of these sequences result in trafficking of the encoded polypeptide to the endoplasmic reticulum through one or more secretory pathways. Some signal peptides are cleaved from the protein by signal peptidase after the proteins are transported.

Additional signal sequences which may be utilized in the present invention include those taught in, for example, databases such as those found at http://www.signalpeptide.de/or http://proline.bic.nus.edu.sg/spdb/. Those described in U.S. Pat. Nos. 8,124,379; 7,413,875 and U.S. Pat. No. 7,385,034 are also within the scope of the invention and the contents of each are incorporated herein by reference in their entirety.

Protein Cleavage Signals and Sites

In exemplary embodiments, polypeptides of the invention (e.g., antigen polypeptides) may include various protein cleavage signals and/or sites.

In one embodiment, the polypeptides of the present invention may include at least one protein cleavage signal containing at least one protein cleavage site. The protein cleavage site may be located at the N-terminus, the C-terminus, at any space between the N- and the C-termini such as, but not limited to, half-way between the N- and C-termini, between the N-terminus and the half way point, between the half way point and the C-terminus, and combinations thereof.

In one embodiment, the polynucleotides of the present invention may be engineered such that the polynucleotide contains at least one encoded protein cleavage signal. The encoded protein cleavage signal may be located in any region including but not limited to before the start codon, after the start codon, before the coding region, within the coding region such as, but not limited to, half way in the coding region, between the start codon and the half way point, between the half way point and the stop codon, after the coding region, before the stop codon, between two stop codons, after the stop codon and combinations thereof.

In one embodiment, the polynucleotides of the present invention may include at least one encoded protein cleavage signal containing at least one protein cleavage site. The encoded protein cleavage signal may include, but is not limited to, a proprotein convertase (or prohormone convertase), thrombin and/or Factor Xa protein cleavage signal.

As a non-limiting example, U.S. Pat. No. 7,374,930 and U.S. Pub. No. 20090227660, herein incorporated by reference in their entireties, use a furin cleavage site to cleave the N-terminal methionine of GLP-1 in the expression product from the Golgi apparatus of the cells. In one embodiment, the polypeptides of the present invention include at least one protein cleavage signal and/or site with the proviso that the polypeptide is not GLP-1.

Insertions and Substitutions

In exemplary embodiments, polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) can include various substitutions and/or insertions.

In one embodiment, the 5′UTR of the polynucleotide may be replaced by the insertion of at least one region and/or string of nucleosides of the same base. The region and/or string of nucleotides may include, but is not limited to, at least 3, at least 4, at least 5, at least 6, at least 7 or at least 8 nucleotides and the nucleotides may be natural and/or unnatural. As a non-limiting example, the group of nucleotides may include 5-8 adenine, cytosine, thymine, a string of any of the other nucleotides disclosed herein and/or combinations thereof.

In one embodiment, the 5′UTR of the polynucleotide may be replaced by the insertion of at least two regions and/or strings of nucleotides of two different bases such as, but not limited to, adenine, cytosine, thymine, any of the other nucleotides disclosed herein and/or combinations thereof. For example, the 5′UTR may be replaced by inserting 5-8 adenine bases followed by the insertion of 5-8 cytosine bases. In another example, the 5′UTR may be replaced by inserting 5-8 cytosine bases followed by the insertion of 5-8 adenine bases.

In one embodiment, the polynucleotide may include at least one substitution and/or insertion downstream of the transcription start site which may be recognized by an RNA polymerase. As a non-limiting example, at least one substitution and/or insertion may occur downstream the transcription start site by substituting at least one nucleic acid in the region just downstream of the transcription start site (such as, but not limited to, +1 to +6). Changes to region of nucleotides just downstream of the transcription start site may affect initiation rates, increase apparent nucleotide triphosphate (NTP) reaction constant values, and increase the dissociation of short transcripts from the transcription complex curing initial transcription (Brieba et al, Biochemistry (2002) 41: 5144-5149; herein incorporated by reference in its entirety). The modification, substitution and/or insertion of at least one nucleoside may cause a silent mutation of the sequence or may cause a mutation in the amino acid sequence.

In one embodiment, the polynucleotide may include the substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 or at least 13 guanine bases downstream of the transcription start site.

In one embodiment, the polynucleotide may include the substitution of at least 1, at least 2, at least 3, at least 4, at least 5 or at least 6 guanine bases in the region just downstream of the transcription start site. As a non-limiting example, if the nucleotides in the region are GGGAGA the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 adenine nucleotides. In another non-limiting example, if the nucleotides in the region are GGGAGA the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 cytosine bases. In another non-limiting example, if the nucleotides in the region are GGGAGA the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 thymine, and/or any of the nucleotides described herein.

In one embodiment, the polynucleotide may include at least one substitution and/or insertion upstream of the start codon. For the purpose of clarity, one of skill in the art would appreciate that the start codon is the first codon of the protein coding region whereas the transcription start site is the site where transcription begins. The polynucleotide may include, but is not limited to, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 or at least 8 substitutions and/or insertions of nucleotide bases. The nucleotide bases may be inserted or substituted at 1, at least 1, at least 2, at least 3, at least 4 or at least 5 locations upstream of the start codon. The nucleotides inserted and/or substituted may be the same base (e.g., all A or all C or all T or all G), two different bases (e.g., A and C, A and T, or C and T), three different bases (e.g., A, C and T or A, C and T) or at least four different bases. As a non-limiting example, the guanine base upstream of the coding region in the polynucleotide may be substituted with adenine, cytosine, thymine, or any of the nucleotides described herein. In another non-limiting example the substitution of guanine bases in the polynucleotide may be designed so as to leave one guanine base in the region downstream of the transcription start site and before the start codon (see Esvelt et al. Nature (2011) 472(7344):499-503; the contents of which is herein incorporated by reference in its entirety). As a non-limiting example, at least 5 nucleotides may be inserted at 1 location downstream of the transcription start site but upstream of the start codon and the at least 5 nucleotides may be the same base type.

Incorporating Post Transcriptional Control Modulators

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may include at least one post transcriptional control modulator. These post transcriptional control modulators may be, but are not limited to, small molecules, compounds and regulatory sequences. As a non-limiting example, post transcriptional control may be achieved using small molecules identified by PTC Therapeutics Inc. (South Plainfield, N.J.) using their GEM™ (Gene Expression Modulation by Small-Moleclues) screening technology.

The post transcriptional control modulator may be a gene expression modulator which is screened by the method detailed in or a gene expression modulator described in International Publication No. WO2006022712, herein incorporated by reference in its entirety. Methods identifying RNA regulatory sequences involved in translational control are described in International Publication No. WO2004067728, herein incorporated by reference in its entirety; methods identifying compounds that modulate untranslated region dependent expression of a gene are described in International Publication No. WO2004065561, herein incorporated by reference in its entirety.

In one embodiment, the polynucleotides of the present invention may include at least one post transcriptional control modulator is located in the 5′ and/or the 3′ untranslated region of the polynucleotides of the present invention.

In another embodiment, the polynucleotides of the present invention may include at least one post transcription control modulator to modulate premature translation termination. The post transcription control modulators may be compounds described in or a compound found by methods outlined in International Publication Nso. WO2004010106, WO2006044456, WO2006044682, WO2006044503 and WO2006044505, each of which is herein incorporated by reference in its entirety. As a non-limiting example, the compound may bind to a region of the 28S ribosomal RNA in order to modulate premature translation termination (See e.g., WO2004010106, herein incorporated by reference in its entirety).

In one embodiment, polynucleotides of the present invention may include at least one post transcription control modulator to alter protein expression. As a non-limiting example, the expression of VEGF may be regulated using the compounds described in or a compound found by the methods described in International Publication Nos. WO2005118857, WO2006065480, WO2006065479 and WO2006058088, each of which is herein incorporated by reference in its entirety.

The polynucleotides of the present invention may include at least one post transcription control modulator to control translation. In one embodiment, the post transcription control modulator may be a RNA regulatory sequence. As a non-limiting example, the RNA regulatory sequence may be identified by the methods described in International Publication No. WO2006071903, herein incorporated by reference in its entirety.

Codon Optimization

The polynucleotides contained in the NAVs of the invention, their regions or parts or subregions may be codon optimized. Codon optimization methods are known in the art and may be useful in efforts to achieve one or more of several goals. These goals include to match codon frequencies in target and host organisms to ensure proper folding, bias GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons or base runs that may impair gene construction or expression, customize transcriptional and translational control regions, insert or remove protein trafficking sequences, remove/add post translation modification sites in encoded protein (e.g. glycosylation sites), add, remove or shuffle protein domains, insert or delete restriction sites, modify ribosome binding sites and mRNA degradation sites, to adjust translational rates to allow the various domains of the protein to fold properly, or to reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art, non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park Calif.) and/or proprietary methods. In one embodiment, the ORF sequence is optimized using optimization algorithms. Codon options for each amino acid are given in Table 21.

TABLE 21 Codon Options Single Letter Amino Acid Code Codon Options Isoleucine I ATT, ATC, ATA Leucine L CTT, CTC, CTA, CTG, TTA, TTG Valine V GTT, GTC, GTA, GTG Phenylalanine F TTT, TTC Methionine M ATG Cysteine C TGT, TGC Alanine A GCT, GCC, GCA, GCG Glycine G GGT, GGC, GGA, GGG Proline P CCT, CCC, CCA, CCG Threonine T ACT, ACC, ACA, ACG Serine S TCT, TCC, TCA, TCG, AGT, AGC Tyrosine Y TAT, TAC Tryptophan W TGG Glutamine Q CAA, CAG Asparagine N AAT, AAC Histidine H CAT, CAC Glutamic acid E GAA, GAG Aspartic acid D GAT, GAC Lysine K AAA, AAG Arginine R CGT, CGC, CGA, CGG, AGA, AGG Selenocysteine Sec UGA in mRNA in presence of Selenocystein insertion element (SECIS) Stop codons Stop TAA, TAG, TGA

Features, which may be considered beneficial in some embodiments of the present invention, may be encoded by regions of the polynucleotide and such regions may be upstream (5′) or downstream (3′) to a region which encodes a polypeptide. These regions may be incorporated into the polynucleotide before and/or after codon optimization of the protein encoding region or open reading frame (ORF). It is not required that a polynucleotide contain both a 5′ and 3′ flanking region. Examples of such features include, but are not limited to, untranslated regions (UTRs), Kozak sequences, an oligo(dT) sequence, and detectable tags and may include multiple cloning sites which may have Xbal recognition.

In some embodiments, a 5′ UTR and/or a 3′ UTR region may be provided as flanking regions. Multiple 5′ or 3′ UTRs may be included in the flanking regions and may be the same or of different sequences. Any portion of the flanking regions, including none, may be codon optimized and any may independently contain one or more different structural or chemical modifications, before and/or after codon optimization.

After optimization (if desired), the polynucleotides components are reconstituted and transformed into a vector such as, but not limited to, plasmids, viruses, cosmids, and artificial chromosomes. For example, the optimized polynculeotide may be reconstituted and transformed into chemically competent E. coli, yeast, neurospora, maize, drosophila, etc. where high copy plasmid-like or chromosome structures occur by methods described herein.

Synthetic polynucleotides and their nucleic acid analogs play an important role in the research and studies of biochemical processes. Various enzyme-assisted and chemical-based methods have been developed to synthesize polynucleotides and nucleic acids, in particular, polynucleotides and nucleic acids featured in the NAVs of the invention, as described infra.

Synthesis: Enzymatic Methods

In Vitro Transcription-Enzymatic Synthesis

cDNA encoding the polynucleotides described herein may be transcribed using an in vitro transcription (IVT) system. The system typically comprises a transcription buffer, nucleotide triphosphates (NTPs), an RNase inhibitor and a polymerase. The NTPs may be manufactured in house, may be selected from a supplier, or may be synthesized as described herein. The NTPs may be selected from, but are not limited to, those described herein including natural and unnatural (modified) NTPs. The polymerase may be selected from, but is not limited to, T7 RNA polymerase, T3 RNA polymerase and mutant polymerases such as, but not limited to, polymerases able to incorporate polynucleotides (e.g., modified nucleic acids).

RNA Polymerases Useful for Synthesis

Any number of RNA polymerases or variants may be used in the synthesis of the polynucleotides of the present invention.

RNA polymerases may be modified by inserting or deleting amino acids of the RNA polymerase sequence. As a non-limiting example, the RNA polymerase may be modified to exhibit an increased ability to incorporate a 2′-modified nucleotide triphosphate compared to an unmodified RNA polymerase (see International Publication WO2008078180 and U.S. Pat. No. 8,101,385; herein incorporated by reference in their entireties).

Variants may be obtained by evolving an RNA polymerase, optimizing the RNA polymerase amino acid and/or nucleic acid sequence and/or by using other methods known in the art. As a non-limiting example, T7 RNA polymerase variants may be evolved using the continuous directed evolution system set out by Esvelt et al. (Nature (2011) 472(7344):499-503; herein incorporated by reference in its entirety) where clones of T7 RNA polymerase may encode at least one mutation such as, but not limited to, lysine at position 93 substituted for threonine (K93T), I4M, A7T, E63V, V64D, A65E, D66Y, T76N, C125R, S128R, A136T, N165S, G175R, H176L, Y178H, F182L, L196F, G198V, D208Y, E222K, S228A, Q239R, T243N, G259D, M267I, G280C, H300R, D351A, A354S, E356D, L360P, A383V, Y385C, D388Y,

S397R, M401T, N410S, K450R, P451T, G452V, E484A, H523L, H524N, G542V, E565K, K577E, K577M, N601S, S684Y, L699I, K713E, N748D, Q754R, E775K, A827V, D851N or L864F. As another non-limiting example, T7 RNA polymerase variants may encode at least mutation as described in U.S. Pub. Nos. 20100120024 and 20070117112; herein incorporated by reference in their entireties. Variants of RNA polymerase may also include, but are not limited to, substitutional variants, conservative amino acid substitution, insertional variants, deletional variants and/or covalent derivatives.

In one embodiment, the polynucleotide may be designed to be recognized by the wild type or variant RNA polymerases. In doing so, the polynucleotide may be modified to contain sites or regions of sequence changes from the wild type or parent polynucleotide.

Polynucleotide or nucleic acid synthesis reactions may be carried out by enzymatic methods utilizing polymerases. Polymerases catalyze the creation of phosphodiester bonds between nucleotides in a polynucleotide or nucleic acid chain. Currently known DNA polymerases can be divided into different families based on amino acid sequence comparison and crystal structure analysis. DNA polymerase I (pol I) or A polymerase family, including the Klenow fragments of E. Coli, Bacillus DNA polymerase I, Thermus aquaticus (Taq) DNA polymerases, and the T7 RNA and DNA polymerases, is among the best studied of these families. Another large family is DNA polymerase α (pol α) or B polymerase family, including all eukaryotic replicating DNA polymerases and polymerases from phages T4 and RB69. Although they employ similar catalytic mechanism, these families of polymerases differ in substrate specificity, substrate analog-incorporating efficiency, degree and rate for primer extension, mode of DNA synthesis, exonuclease activity, and sensitivity against inhibitors.

DNA polymerases are also selected based on the optimum reaction conditions they require, such as reaction temperature, pH, and template and primer concentrations. Sometimes a combination of more than one DNA polymerases is employed to achieve the desired DNA fragment size and synthesis efficiency. For example, Cheng et al. increase pH, add glycerol and dimethyl sulfoxide, decrease denaturation times, increase extension times, and utilize a secondary thermostable DNA polymerase that possesses a 3′ to 5′ exonuclease activity to effectively amplify long targets from cloned inserts and human genomic DNA (Cheng et al., PNAS, Vol. 91, 5695-5699 (1994), the contents of which are incorporated herein by reference in their entirety). RNA polymerases from bacteriophage T3, T7, and SP6 have been widely used to prepare RNAs for biochemical and biophysical studies. RNA polymerases, capping enzymes, and poly-A polymerases are disclosed in the copending application No. PCT/US2013/054635 (M032), the contents of which are incorporated herein by reference in their entirety.

In one embodiment, the RNA polymerase which may be used in the synthesis of the chimeric polynucleotides described herein is a Syn5 RNA polymerase (see Zhu et al. Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety). The Syn5 RNA polymerase was recently characterized from marine cyanophage Syn5 by Zhu et al. where they also identified the promoter sequence (see Zhu et al. Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety). Zhu et al. found that Syn5 RNA polymerase catalyzed RNA synthesis over a wider range of temperatures and salinity as compared to T7 RNA polymerase. Additionally, the requirement for the initiating nucleotide at the promoter was found to be less stringent for Syn5 RNA polymerase as compared to the T7 RNA polymerase making Syn5 RNA polymerase promising for RNA synthesis.

In one embodiment, a Syn5 RNA polymerase may be used in the synthesis of the chimeric polynucleotides described herein. As a non-limiting example, a Syn5 RNA polymerase may be used in the synthesis of the chimeric polynucleotide requiring a precise 3′-termini.

In one embodiment, a Syn5 promoter may be used in the synthesis of the chimeric polynucleotides. As a non-limiting example, the Syn5 promoter may be 5′-ATTGGGCACCCGTAAGGG-3′ (SEQ ID NO: 966) as described by Zhu et al. (Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety).

In one embodiment, a Syn5 RNA polymerase may be used in the synthesis of chimeric polynucleotides comprising at least one chemical modification described herein and/or known in the art. (see e.g., the incorporation of pseudo-UTP and 5Me-CTP described in Zhu et al. Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety).

In one embodiment, the chimeric polynucleotides described herein may be synthesized using a Syn5 RNA polymerase which has been purified using modified and improved purification procedure described by Zhu et al. (Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety).

Various tools in genetic engineering are based on the enzymatic amplification of a target gene which acts as a template. For the study of sequences of individual genes or specific regions of interest and other research needs, it is necessary to generate multiple copies of a target gene from a small sample of polynucleotides or nucleic acids. Such methods may be applied in the manufacture of the polynucleotides of the invention.

Polymerase chain reaction (PCR) has wide applications in rapid amplification of a target gene, as well as genome mapping and sequencing. The key components for synthesizing DNA comprise target DNA molecules as a template, primers complementary to the ends of target DNA strands, deoxynucleoside triphosphates (dNTPs) as building blocks, and a DNA polymerase. As PCR progresses through denaturation, annealing and extension steps, the newly produced DNA molecules can act as a template for the next circle of replication, achieving exponentially amplification of the target DNA. PCR requires a cycle of heating and cooling for denaturation and annealing. Variations of the basic PCR include, but are not limited to, asymmetric PCR (See e.g., Innis et al., PNAS, vol. 85, 9436-9440 (1988), the contents of which are incorporated herein by reference in their entirety), inverse PCR (see e.g., Ochman et al., Genetics, vol. 120(3), 621-623, (1988), the contents of which are incorporated herein by reference in their entirety), and reverse transcription PCR (RT-PCR) (see e.g., Freeman et al., BioTechniques, vol. 26(1), 112-22, 124-5 (1999), the contents of which are incorporated herein by reference in their entirety). In RT-PCR, a single stranded RNA is the desired target and is converted to a double stranded DNA first by reverse transcriptase.

A variety of isothermal in vitro nucleic acid amplification techniques have been developed as alternatives or complements of PCR. For example, strand displacement amplification (SDA) is based on the ability of a restriction enzyme to form a nick (Walker et al., PNAS, vol. 89, 392-396 (1992), the contents of which are incorporated herein by reference in their entirety). A restriction enzyme recognition sequence is inserted into an annealed primer sequence. Primers are extended by a DNA polymerase and dNTPs to form a duplex. Only one strand of the duplex is cleaved by the restriction enzyme. Each single strand chain is then available as a template for subsequent synthesis. SDA does not require the complicated temperature control cycle of PCR.

Nucleic acid sequence-based amplification (NASBA), also called transcription mediated amplification (TMA), is also an isothermal amplification method that utilizes a combination of DNA polymerase, reverse transcriptase, RNAse H, and T7 RNA polymerase (Compton, Nature, vol. 350, 91-92 (1991), the contents of which are incorporated herein by reference in their entirety). A target RNA is used as a template and a reverse transcriptase synthesizes its complementary DNA strand. RNAse H hydrolyzes the RNA template, making space for a DNA polymerase to synthesize a DNA strand complementary to the first DNA strand which is complementary to the RNA target, forming a DNA duplex. T7 RNA polymerase continuously generates complementary RNA strands of this DNA duplex. These RNA strands act as templates for new cycles of DNA synthesis, resulting in amplification of the target gene.

Rolling-circle amplification (RCA) amplifies a single stranded circular polynucleotide and involves numerous rounds of isothermal enzymatic synthesis where Φ29 DNA polymerase extends a primer by continuously progressing around the polynucleotide circle to replicate its sequence over and over again. Therefore, a linear copy of the circular template is achieved. A primer can then be annealed to this linear copy and its complementary chain can be synthesized (Lizardi et al., Nature Genetics, vol. 19, 225-232 (1998), the contents of which are incorporated herein by reference in their entirety). A single stranded circular DNA can also serve as a template for RNA synthesis in the presence of an RNA polymerase (Daubendiek et al., JACS, vol. 117, 7818-7819 (1995), the contents of which are incorporated herein by reference in their entirety). An inverse rapid amplification of cDNA ends (RACE) RCA is described by Polidoros et al. (BioTechniques, vol. 41, 35-42 (2006), the contents of which are incorporated herein by reference in their entirety). A messenger RNA (mRNA) is reverse transcribed into cDNA, followed by RNAse H treatment to separate the cDNA. The cDNA is then circularized by CircLigase into a circular DNA. The amplification of the resulting circular DNA is achived with RCA.

Any of the foregoing methods may be utilized in the manufacture of one or more regions of the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention).

Assembling polynucleotides or nucleic acids (e.g., antigen-encoding polynucleotides or nucleic acids) by a ligase is also widely used. DNA or RNA ligases promote intermolecular ligation of the 5′ and 3′ ends of polynucleotide chains through the formation of a phosphodiester bond. Ligase chain reaction (LCR) is a promising diagnosing technique based on the principle that two adjacent polynucleotide probes hybridize to one strand of a target gene and couple to each other by a ligase. If a target gene is not present, or if there is a mismatch at the target gene, such as a single-nucleotide polymorphism (SNP), the probes cannot ligase (Wiedmann et al., PCR Methods and Application, vol. 3 (4), s51-s64 (1994), the contents of which are incorporated herein by reference in their entirety). LCR may be combined with various amplification techniques to increase sensitivity of detection or to increase the amount of products if it is used in synthesizing polynucleotides and nucleic acids.

Several library preparation kits for nucleic acids are now commercially available. They include enzymes and buffers to convert a small amount of nucleic acid samples into an indexed library for downstream applications. For example, DNA fragments may be placed in a NEBNEXT® ULTRA™ DNA Library Prep Kit by NEWENGLAND BIOLABS® for end preparation, ligation, size selection, clean-up, PCR amplification and final clean-up.

Continued development is going on to improvement the amplification techniques. For example, U.S. Pat. No. 8,367,328 to Asada et al. the contents of which are incorporated herein by reference in their entirety, teaches utilizing a reaction enhancer to increase the efficiency of DNA synthesis reactions by DNA polymerases. The reaction enhancer comprises an acidic substance or cationic complexes of an acidic substance. U.S. Pat. No. 7,384,739 to Kitabayashi et al. the contents of which are incorporated herein by reference in their entirety, teaches a carboxylate ion-supplying substance that promotes enzymatic DNA synthesis, wherein the carboxylate ioin-supplying substance is selected from oxalic acid, malonic acid, esters of oxalic acid, esters of malonic acid, salts of malonic acid, and esters of maleic acid. U.S. Pat. No. 7,378,262 to Sobek et al. the contents of which are incorporated herein by reference in their entirety, discloses an enzyme composition to increase fidelity of DNA amplifications. The composition comprises one enzyme with 3′ exonuclease activity but no polymerase activity and another enzyme that is a polymerase. Both of the enzymes are thermostable and are reversibly modified to be inactive at lower temperatures.

U.S. Pat. No. 7,550,264 to Getts et al. teaches multiple round of synthesis of sense RNA molecules are performed by attaching oligodeoxynucleotides tails onto the 3′ end of cDNA molecules and initiating RNA transcription using RNA polymerase, the contents of which are incorporated herein by reference in their entirety. US Pat. Publication No. 2013/0183718 to Rohayem teaches RNA synthesis by RNA-dependent RNA polymerases (RdRp) displaying an RNA polymerase activity on single-stranded DNA templates, the contents of which are incorporated herein by reference in their entirety. Oligonucleotides with non-standard nucleotides may be synthesized with enzymatic polymerization by contacting a template compring non-standard nucleotides with a mixture of nucleotides that are complementary to the nucleotides of the template as disclosed in U.S. Pat. No. 6,617,106 to Benner, the contents of which are incorporated herein by reference in their entirety.

Synthesis: Solid-Phase Chemical Synthesis

Chimeric polynucleotides or circular polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be manufactured in whole or in part using solid phase techniques.

Solid-phase chemical synthesis of polynucleotides or nucleic acids is an automated method wherein molecules are immobilized on a solid support and synthesized step by step in a reactant solution. Impurities and excess reagents are washed away and no purification is required after each step. The automation of the process is amenable on a computer-controlled solid-phase synthesizer. Solid-phase synthesis allows rapid production of polynucleotides or nucleic acids in a relatively large scale that leads to the commercial availability of some polynucleotides or nucleic acids. Furthermore, it is useful in site-specific introduction of chemical modifications in the polynucleotide or nucleic acid sequences. It is an indispensable tool in designing modified derivatives of natural nucleic acids.

In automated solid-phase synthesis, the chain is synthesized in 3′ to 5′ direction. The hydroxyl group in the 3′ end of a nucleoside is tethered to a solid support via a chemically cleavable or light-cleavable linker. Activated nucleoside monomers, such as 2′-deoxynucleosides (dA, dC, dG and T), ribonucleosides (A, C, G, and U), or chemically modified nucleosides, are added to the support-bound nucleoside sequentially. Currently most widely utilized monomers are the 3′-phophoramidite derivatives of nucleoside building blocks. The 3′ phosphorus atom of the activated monomer couples with the 5′ oxygen atom of the support-bound nucleoside to form a phosphite triester. To prevent side reactions, all functional groups not involved in the coupling reaction, such as the 5′ hydroxyl group, the hydroxyl group on the 3′ phosphorus atom, the 2′ hydroxyl group in ribonucleosides monomers, and the amino groups on the purine or pyrimidine bases, are all blocked with protection groups. The next step involves oxidation of the phosphite triester to form a phosphate triester or phosphotriester, where the phosphorus atom is pentavalent. The protection group on the 5′ hydroxyl group at the end of the growing chain is then removed, ready to couple with an incoming activated monomer building block. At the end of the synthesis, a cleaving agent such as ammonia or ammonium hydroxide is added to remove all the protecting groups and release the polynucleotide chains from the solid support. Light may also be applied to cleave the polynucleotide chain. The product can then be further purified with high pressure liquid chromatography (HPLC) or electrophoresis.

In solid-phase synthesis, the polynucleotide chain is covalently bound to the solid support via its 3′ hydroxyl group. The solid supports are insoluble particles also called resins, typically 50-200 μm in diameter. Many different kinds of resins are now available, as reviewed in “Solid-phase supports for polynucleotide synthesis” by Guzaev (Guzaev, Current Protocols in Nucleic Acid Chemistry, 3.1.1-3.1.60 (2013), the contents of which are incorporated herein by reference in their entirety). The most common materials for the resins include highly cross-linked polystyrene beads and controlled pore glass (CPG) beads. The surface of the beads may be treated to have functional groups, such as amino or aminomethyl groups that can be used as anchoring points for linkers to tether nucleosides. They can be implemented in columns, multi-well plates, microarrays or microchips. The column-based format allows relatively large scale synthesis of the polynucleotides or nucleic acids. The resins are held between filters in columns that enable all reagents and solvents to pass through freely. Multi-well plates, microarrays, or microchips are designed specifically for cost-effective small scale synthesis. Up to a million polynucleotides can be produced on a single microarray chip. However, the error rates of microchip-based synthesis are higher than traditional column-based methods (Borovkov et al., Nucleic Acids Research, vol. 38(19), e180 (2010), the contents of which are incorporated herein by reference in their entirety). Multi-well plates allow parallel synthesis of polynucleotides or nucleic acids with different sequences simultaneously (Sindelar, et al., Nucleic Acids Research, vol. 23, 982-987 (1995), the contents of which are incorporated herein by reference in their entirety). The loading on the solid supports is limited. In addition, as the extension progresses, the morphology and bulkiness of the growing chains on the solid supports might hinder the incoming monomers from reacting with the terminal group of the growing chains. Therefore, the number of monomers that can be added to the growing chain is also limited.

Linkers are attached to the solid support for further extension of the chain. They are stable to all the reagents used in the synthesis process, except in the end of the synthesis when the chain is detached from the solid support. Solid supports with a specific nucleoside linker, i.e., A, C, dT, G, or U, can be used to prepare polynucleotides with A, C, T, G, or U as the first nucleotide in the sequence, respectively. Universal solid supports with non-nucleoside linkers can be used for all polynucleotide sequences (U.S. Pat. No. 6,653,468 to Guzaev et al., the contents of which are incorporated herein by reference in their entirety). Various non-nucleoside linkers have been developed for universal supports, a lot of them with two vicinal hydroxyl groups. For example, a succinyl group is a frequently used linker.

As used herein, a linker refers to a group of atoms, e.g., 10-1,000 atoms, and can be comprised of the atoms or groups such as, but not limited to, carbon, amino, alkylamino, oxygen, sulfur, sulfoxide, sulfonyl, carbonyl, and imine. The linker can be attached to a modified nucleoside or nucleotide on the nucleobase or sugar moiety. A linker may be nucleic acid based or non-nucleosidic. The linker may be of sufficient length as to not interfere with incorporation into a nucleic acid sequence. The linker can be used for any useful purpose, such as to form multimers (e.g., through linkage of two or more chimeric polynucleotides molecules) or conjugates, as well as to administer a therapeutic molecule or incorporate a label, as described herein. Examples of chemical groups that can be incorporated into the linker include, but are not limited to, alkyl, alkenyl, alkynyl, amido, amino, ether, thioether, ester, alkylene, heteroalkylene, aryl, or heterocyclyl, each of which can be optionally substituted, as described herein. Examples of linkers include, but are not limited to, unsaturated alkanes, polyethylene glycols (e.g., ethylene or propylene glycol monomeric units, e.g., diethylene glycol, dipropylene glycol, triethylene glycol, tripropylene glycol, tetraethylene glycol, or tetraethylene glycol), and dextran polymers and derivatives thereof. Other examples include, but are not limited to, cleavable moieties within the linker, such as, for example, a disulfide bond (—S—S—) or an azo bond (—N═N—), which can be cleaved using a reducing agent or photolysis. Non-limiting examples of a selectively cleavable bond include an amido bond can be cleaved for example by the use of tris(2-carboxyethyl)phosphine (TCEP), or other reducing agents, and/or photolysis, as well as an ester bond can be cleaved for example by acidic or basic hydrolysis.)

Besides the functional groups on the activated monomer and the growing chain needed for the coupling reaction to extend the chain, all other functional groups need to be protected to avoid side reactions. The conditions for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found and/or described, for example, in Greene, et al. (Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, the contents of which is incorporated herein by reference in its entirety.) For example, the 5′ hydroxyl group on the activated nucleoside phosphoramidite monomers may be protected with 4,4′-dimethoxytrityl (DMT) and the hydroxyl group on the phosphorus atom may be protected with 2-cyanoethyl. The exocyclic amino groups on the A, C, G bases may be protected with acyl groups.

In a solid-phase synthesis system, the reactivity of the activated monomers is important, because of the heterogeneity of the media. A majority of solid-phase synthesis uses phosphoramidite nucleosides, the mechanism of which is discussed above. Another activated monomer example is nucleoside H-phosphonates (Abramova, Molecules, vol. 18, 1063-1075 (2013), the contents of which are incorporated herein by reference in their entirety). A large excess of reagents, such as monomers, oxidizing agents, and deprotection agents, is required in order to ensure high yields in the solid-phase synthesis system.

Scientific studies and research are going on to further improve the solid-phase synthesis method. For example, instead of the well-established 3′-to-5′ synthesis, U.S. Pat. No. 8,309,707 and US Pat. Publication No. 2013/0072670 to Srivastava et al. disclosed a 5′-to-3′ synthesis of RNA utilizing a novel phosphoramidite and a novel nucleoside derivative, thereby allowing easy modifications of the synthetic RNA at the 3′ end. PCT application WO2013123125 to Church et al. the contents of which are incorporated herein by reference in their entirety, describes assembly of a target nucleic acid sequence from a plurality of subsequences, wherein resins with the subsequences are placed in an emulsion droplet. The subsequences are cleaved off the resins and assemble within the emulsion droplet. To reduce the cost of solid supports, a reusable CPG solid support has been developed with a hydroquinone-O, O′-diacetic acid linker (Q-linker) (Pon et al., Nucleic Acid Research, vol. 27, 1531-1538 (1999), the contents of which are incorporated herein by reference in their entirety).

New protecting groups for solid-phase synthesis have also been developed. Nagat et al. has successfully synthesized 110-nt-long RNA with the sequence of a candidate precursor microRNA by using 2-cyanoethoxymethyl (CEM) as the 2′-hydroxy protecting group (Shiba et al., Nucleic Acids Research, vol. 35, 3287-3296 (2007), the contents of which are incorporated herein by reference in their entirety). Also with CEM as 2′-O-protecting group, a 130-nt mRNA has been synthesized encoding a 33-amino acid peptide that includes the sequence of glucagon-like peptide-1 (GLP-1). The biological activity of the artificial 130-nt mRNA is shown by producing GLP-1 in a cell-free protein synthesis system and in Chinese hamster ovary (CHO) cells (Nagata et al., Nucleic Acids Research, vol. 38(21), 7845-7857 (2010), the contents of which are incorporated herein by reference in their entirety). Novel protecting groups for solid-phase synthesis monomers include, but are not limited to, carbonate protecting group disclosed in U.S. Pat. No. 8,309,706 to Dellinger et al., orthoester-type 2′ hydroxyl protecting group and an acyl carbonate-type hydroxyl protecting group disclosed in U.S. Pat. No. 8,242,258 to Dellinger et al., 2′-hydroxyl thiocarbon protecting group disclosed in U.S. Pat. No. 8,202,983 to Dellinger et al., 2′-silyl containing thiocarbonate protecting group disclosed in U.S. Pat. No. 7,999,087 to Dellinger et al., 9-fluorenylmethoxycarbonyl (FMOS) derivatives as an amino protecting group disclosed in U.S. Pat. No. 7,667,033 to Alvarado, fluoride-labile 5′silyl protecting group disclosed in U.S. Pat. No. 5,889,136 to Scaringe et al., and pixyl protecting groups disclosed in US Pat. Publication No. 2008/0119645 to Griffey et al., the contents of which are incorporated herein by reference in their entirety. US Pat. Publication No. 2011/0275793 to Debart et al. teaches RNA synthesis using a protecting group of the hyoxyls in position 2′ of the ribose that can be removed by a base, the contents of which are incorporated herein by reference in their entirety.

Novel solid supports include polymers made from monomers comprising protected hydroxypolyC₂₋₄alkyleneoxy chain attached to a polymerizable unit taught in U.S. Pat. No. 7,476,709 to Moody et al., the contents of which are incorporated herein by reference in their entirety.

Synthesis: Liquid Phase Chemical Synthesis

The synthesis of chimeric polynucleotides or circular polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) by the sequential addition of monomer building blocks may be carried out in a liquid phase. A covalent bond is formed between the monomers or between a terminal functional group of the growing chain and an incoming monomer. Functional groups not involved in the reaction must be temporarily protected. After the addition of each monomer building block, the reaction mixture has to be purified before adding the next monomer building block. The functional group at one terminal of the chain has to be deprotected to be able to react with the next monomer building blocks. A liquid phase synthesis is labor- and time-consuming and cannot not be automated. Despite the limitations, liquid phase synthesis is still useful in preparing short polynucleotides in a large scale. Because the system is homogenous, it does not require a large excess of reagents and is cost-effective in this respect.

Synthesis: Combination of Synthetic Methods

The synthetic methods discussed above each has its own advantages and limitations. Attempts have been conducted to combine these methods to overcome the limitations. Such combinations of methods are within the scope of the present invention.

Short polynucleotide chains with 2-4 nucleotides may be prepared in liquid phase followed by binding to a solid support for extension reactions by solid phase synthesis. A high efficiency liquid phase (HELP) synthesis is developed that uses monomethyl ether of polyethylene glycol (MPEG) beads as a support for the monomer building blocks. MPEG is soluble in methylene chloride and pyridine solvents but precipitates in a diethyl ether solvent. By choosing an appropriate solvent, the coupling reaction between monomers or between a growing chain and an incoming monomer bound on MPEG can be carried out in a homogenous liquid phase system. The mixture can then be washed with a diethyl ether solvent to easily precipitate and purify the product (Bonora et al., Nucleic Acids Research, vol. 18, 3155-3159 (1990), the contents of which are incorporated herein by reference in their entirety). U.S. Pat. No. 8,304,532 to Adamo et al., the contents of which are incorporated herein in their entirety, teaches a solution phase oligonucleotide synthesis where at least some of the reagents are solid supported.

The use of solid-phase or liquid-phase chemical synthesis in combination with enzymatic ligation provides an efficient way to generate long chain polynucleotides that cannot be obtained by chemical synthesis alone. Moore and Sharp describe preparing RNA fragments 10- to 20-nt long by chemical synthesis, to which site-specific modifications may be introduced, annealing the fragments to a cDNA bridge, and then assemble the fragments with T4 DNA ligase (Moore et al., Science, vol. 256, 992-997 (1992), the contents of which are incorporated herein by reference in their entirety).

A solid-phase synthesizer may produce enough polynucleotides or nucleic acids with good purity to preform PCR and other amplification techniques. Agilent Technologies have developed microarrays that are commercially available. Polynucleotides may be synthesized on a microarray substrate, cleaved by a strong base or light, followed by PCR amplification to generate a library of polynucleotides (Cleary et al., Nature Methods, vol. 1(3), 241-247 (2004), the contents of which are incorporated herein by reference in their entirety).

Synthesis: Small Region Synthesis

Regions or subregions of the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may comprise small RNA molecules such as siRNA, and therefore may be synthesized in the same manner. There are several methods for preparing siRNA, such as chemical synthesis using appropriately protected ribonucleoside phosphoramidites, in vitro transcription, siRNA expression vectors, and PCR expression cassettes. Sigma-Aldrich® is one of the siRNA suppliers and synthesizes their siRNA using ribonucleoside phosphoramidite monomers protected at the 2′ position with a t-butylmethylsilyl (TBDMS) group. The solid-phase chemical synthesis is carried out with SIGMA-ALDRICH®'s Ultra Fast Parallel Synthesis (UFPS) and Ultra Fast Parallel Deprotection (UFPD) to achieve high coupling efficiency and fast deprotection. The final siRNA products may be purified with HPLC or PAGE. Such methods may be used to synthesize regions or subregions of chimeric polynucleotides.

In vitro transcription and expression from a vector or a PCR-generated siRNA cassette require appropriate templates to produce siRNAs. The commercially available AMBION® SILENCER® siRNA construction kit produces siRNA by in vitro transcription of DNA templates and contains the enzymes, buffers, primers needed. Such methods may be used to synthesize regions or subregions of chimeric polynucleotides.

Synthesis: Ligation of Polynucleotide Regions or Subregions

Polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) such as chimeric polynucleotides and/or circular polynucleotides may be prepared by ligation of one or more regions or subregions.

Ligation is an indispensable tool for assembling polynucleotide or nucleic acid fragments into larger constructs. DNA fragments can be joined by a ligase catalyzed reaction to create recombinant DNA with different functions. Two oligodeoxynucleotides, one with a 5′ phosphoryl group and another with a free 3′ hydroxyl group, serve as substrates for a DNA ligase. Oligodexoynucleotides with fluorescent or chemiluminescent labels may also serve as DNA ligase substrates (Martinelli et al., Clinical Chemistry, vol. 42, 14-18 (1996), the contents of which are incorporated herein by reference in their entirety). RNA ligases such as T4 RNA ligase catalyze the formation of a phosphodiester bond between two single stranded oligoribonucleotides or RNA fragments. Copies of large DNA constructs have been synthesized with a combination of polynucleotide fragments, thermostable DNA polymerases, and DNA ligases. US Pat. Publication No. 2009/0170090 to Ignatov et al., the contents of which are incorporated herein by reference in their entirety, discloses improving PCT, especially enhancing yield of a long distance PCR and/or a low copy DNA template PCR amplication, by using a DNA ligase in addition to a DNA polymerase.

Ligases may be used with other enzymes to prepare desired chimeric polynucleotide or nucleic acid molecules and to perform genome analysis. For example, ligation-mediated selective PCR amplification is disclosed in EP Pat. Pub. No. 0735144 to Kato. Complementary DNAs (cDNAs) reverse-transcribed from tissue- or cell-derived RNA or DNA are digested into fragments with type IIS restriction enzymes the contents of which are incorporated herein by reference in their entirety. Biotinylated adapter sequences are attached to the fragments by E. coli DNA ligases. The biotin-labeled DNA fragments are then immobilized onto streptavidin-coated beads for downstream analysis.

A ligation splint or a ligation splint oligo is an oligonucleotide that is used to provide an annealing site or a ligation template for joining two ends of one nucleic acid, i.e., intramolecular joining, or two ends of two nucleic acids, i.e., intermolecular joining, using a ligase or another enzyme with ligase activity. The ligation splint holds the ends adjacent to each other and creates a ligation junction between the 5′-phosphorylated and a 3′-hydroxylated ends that are to be ligated.

In one embodiment, a splint-mediated ligation or splint ligation method may be used to synthesize the chimeric polynucleotides described herein. The chimeric polynucleotide may be assembled using a method that does not rely on the presence of restriction endonuclease cleavage sites such as the method described in International Patent Publication No. WO2012138453, the contents of which are herein incorporated by reference in its entirety. Splint-mediated ligation allows for the rapid synthesis of the construct using controlled concatenation and without the need or with limited need for the introduction of restriction sites at the joining regions. As a non-limiting example, splint ligation may be used to add at least one untranslated region to a coding region of the chimeric polynucleotide. In one embodiment, splint ligation may be used in combination with other synthesis methods in the synthesis of the chimeric polynucleotides described herein.

If the 5′-phosphorylated and the 3′-hydroxyl ends of nucleic acids are ligated when the ends are annealed to a ligation splint so that the ends are adjacent, enzymes such as, but not limited to, T4 DNA ligase, AMPLIGASE® DNA Ligase (EPICENTRE® Technologies), Tth DNA ligase, Tfl DNA ligase, or Tsc DNA Ligase (Prokaria) can be used. Farugui IN U.S. Pat. No. 6,368,801 (the contents of which is incorporated by reference in its entirety) describes that T4 RNA ligase can efficiently ligate ends of DNA molecules that are adjacent to each other when hybridized to an RNA splint. Thus, T4 RNA ligase is a suitable ligase for joining DNA ends with a ligation splint oligo comprising RNA or modified RNA. Examples of RNA splints include modified RNA containing 2′-fluorine-CTP (2′-F-dCTP) and 2′-fluorine-UTP (2′-F-dUTP) made using the DURASCRIBE® T7 Transcription Kit (EPICENTRE® Technologies) disclosed in U.S. Pat. No. 8,137,911 and US Pat. Publication 2012/0156679 to Dahl et al, the contents of each of which are incorporated herein by reference in their entirety. The modified RNA produced from DURASCRIBE® T7 Transcription kit is completely resistant to RNase A digestion. DNA splint and DNA ligase may be used to generate RNA-protein fusions disclosed in U.S. Pat. No. 6,258,558 to Szostak et al., the contents of which are incorporated herein by reference in their entirety.

For intramolecular ligation of linear ssDNA, U.S. Pat. No. 7,906,490 to Kool et al. teaches constructing a 83-nucleotide circle by making linear oligodeoxynucleotides fragments on a DNA synthesizer followed by ligation with T4 DNA ligase and two 30 nucleotide splint oligonucleotides. Circulation of linear sense promoter-containing cDNA is disclosed in US Pat. Publication No. 2012/0156679 to Dahl et al., the contents of which are incorporated herein by reference in their entirety. THERMOPHAGE™ ssDNA ligase (Prokazyme), which is derived from phage TS2126 that infects Themus scotoductus, catalyzes ATP-dependent intra- and inter-molecular ligation of DNA and RNA.

The solid-phase chemical synthesis method that uses phosphoramidite monomers is limited to produce DNA molecules with short strands. The purity of the DNA products and the yield of reactions become poor when the length exceeds 150 bases. For the synthesis of long polynucleotides in high yields, it is more convenient to use enzymatic ligation method in tandem with chemical synthesis. For example, Moore and Sharp describe preparing RNA fragments 10- to 20-nt long by chemical synthesis, to which site-specific modifications may be introduced, annealing the fragments to a cDNAsplint, and then assemble the fragments with T4 DNA ligase (Moore et al., Science, vol. 256, 992-997 (1992), the contents of which are incorporated herein by reference in their entirety). Ligation reactions of oligoribonucleotides with T4 RNA ligase and a DNA splint or a polyribonucleotide to generate large, synthetic RNAs are described in Bain et al., Nucleic Acids Research, vol. 20(16), 4372 (1992), Stark et al., RNA, vol. 12, 2014-2019 (2006), and US Pat. Application No. 2005/0130201 to Deras et al., the contents of each of which are incorporated herein by reference in their entirety. 5′-cap and 3′-polyA tail are often added by enzymatic addition to an oligonucleotide synthesized with solid-phase methods. As a non-limiting example, a synthetic capped 42-mer mRNA has been synthesized in three fragments enzymatically ligated as described by Iwase et al. (Nucleic Acids Research, vol. 20, 1643-1648 (1992), the contents of which are incorporated herein by reference in their entirety). As another example, a 16.3-kilobase mouse mitochondrial genome has been produced from 600 overlapping 60-mer polynucleotides. The method cycles between in vitro recombination and amplification may be repeated until the desired length is reached (Gibson et al., Nature Methods, vol. 7, 901-903 (2010), the contents of which are incorporated herein by reference in their entirety). The assembly of a 1.08 megabase Mycoplasma mycoides JCVI-syn1.0 genome has also been reported. As a non-limiting example, 1080 bp cassettes are produced by assembling polynucleotide fragments chemically generated from a polynucleotide synthesizer. The genome is then assembled in three stages by transformation and homologous recombination in yeast (Gibson, et al., Science, vol. 329, 52-56 (2010), the contents of which are incorporated herein by reference in their entirety).

Studies have been conducted to join short DNA fragments with chemical linkers. ‘Click’ chemistry or ‘click’ ligation, the cycloaddition reaction between azide and alkyne, has gained a lot of interest because of its advantages such as mild reaction condition, high yields, and inoffensive byproducts. ‘Click’ chemistry is reviewed by Nwe et al. in Cancer Biotherapy and Radiopharmaceuticals, vol. 24(3), 289-302 (2009), the contents of which are incorporated here by reference for their entirety. DNA constructs up to 300 bases in length have been produced with click ligation and longer sequences are feasible. Demonstrated with PCR data, various DNA polymerases are able to amplify the synthesized DNA constructs made by click ligation despite the triazole linkers between the fragments resulting from the cycloaddition reaction. In vitro transcription and rolling circle amplification can also be performed on the synthesized DNA constructs. Hairpin ribozymes up to 100 nucleotides in length and cyclic mini-DNA duplexes have also been prepared with click ligation (El-Sagheer et al., Accounts of Chemical Research, vol. 45(8), 1258-1267 (2012), the contents of which are incorporated herein by reference in their entirety).

Sequential ligation can be performed on a solid substrate. For example, initial linker DNA molecules modified with biotin at the end are attached to streptavidin-coated beads. The 3′-ends of the linker DNA molecules are complimentary with the 5′-ends of the incoming DNA fragments. The beads are washed and collected after each ligation step and the final linear constructs are released by a meganuclease. This method allows rapid and efficient assembly of genes in an optimized order and orientation. (Takita, DNA Research, vol. 20(4), 1-10 (2013), the contents of which are incorporated herein by reference in their entirety). Labeled polynucleotides synthesized on solid-supports are disclosed in US Pat. Pub. No. 2001/0014753 to Soloveichik et al. and US Pat. Pub. No. 2003/0191303 to Vinayak et al., the contents of which are incorporated herein by reference for their entirety.

Quantification

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be quantified in exosomes or when derived from one or more bodily fluid. As used herein “bodily fluids” include peripheral blood, serum, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowper's fluid or pre-ejaculatory fluid, sweat, fecal matter, hair, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, and umbilical cord blood. Alternatively, exosomes may be retrieved from an organ selected from the group consisting of lung, heart, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colon, breast, prostate, brain, esophagus, liver, and placenta.

In the exosome quantification method, a sample of not more than 2 mL is obtained from the subject and the exosomes isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, microfluidic separation, or combinations thereof. In the analysis, the level or concentration of a polynucleotide may be an expression level, presence, absence, truncation or alteration of the administered construct. It is advantageous to correlate the level with one or more clinical phenotypes or with an assay for a human disease biomarker. The assay may be performed using construct specific probes, cytometry, qRT-PCR, real-time PCR, PCR, flow cytometry, electrophoresis, mass spectrometry, or combinations thereof while the exosomes may be isolated using immunohistochemical methods such as enzyme linked immunosorbent assay (ELISA) methods. Exosomes may also be isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, microfluidic separation, or combinations thereof.

These methods afford the investigator the ability to monitor, in real time, the level of polynucleotides remaining or delivered. This is possible because the polynucleotides of the present invention differ from the endogenous forms due to the structural or chemical modifications.

In one embodiment, the polynucleotide may be quantified using methods such as, but not limited to, ultraviolet visible spectroscopy (UV/Vis). A non-limiting example of a UV/Vis spectrometer is a NANODROP® spectrometer (ThermoFisher, Waltham, Mass.). The quantified polynucleotide may be analyzed in order to determine if the polynucleotide may be of proper size, check that no degradation of the polynucleotide has occurred. Degradation of the polynucleotide may be checked by methods such as, but not limited to, agarose gel electrophoresis, HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC), liquid chromatography-mass spectrometry (LCMS), capillary electrophoresis (CE) and capillary gel electrophoresis (CGE).

Purification

Purification of the polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) described herein may include, but is not limited to, polynucleotide clean-up, quality assurance and quality control. Clean-up may be performed by methods known in the arts such as, but not limited to, AGENCOURT® beads (Beckman Coulter Genomics, Danvers, Mass.), poly-T beads, LNA™ oligo-T capture probes (EXIQON® Inc, Vedbaek, Denmark) or HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC). The term “purified” when used in relation to a polynucleotide such as a “purified polynucleotide” refers to one that is separated from at least one contaminant. As used herein, a “contaminant” is any substance which makes another unfit, impure or inferior. Thus, a purified polynucleotide (e.g., DNA and RNA) is present in a form or setting different from that in which it is found in nature, or a form or setting different from that which existed prior to subjecting it to a treatment or purification method.

A quality assurance and/or quality control check may be conducted using methods such as, but not limited to, gel electrophoresis, UV absorbance, or analytical HPLC.

In another embodiment, the polynucleotides may be sequenced by methods including, but not limited to reverse-transcriptase-PCR.

IV. Modifications

In exemplary embodiments, polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) can include various substitutions and/or insertions.

The data presented in the Examples demonstrate significant enhanced immune responses using the formulations of the invention. The data demonstrated the effectiveness of both chemically modified and unmodified RNA vaccines of the invention. Surprisingly, in contrast to prior art reports that it was preferable to use chemically unmodified mRNA formulated in a carrier for the production of vaccines, it was discovered herein that chemically modified mRNA-LNP vaccines required a much lower effective mRNA dose than unmodified mRNA, i.e., tenfold less than unmodified mRNA.

Additionally, a study described herein involved intravenous (IV), intramuscular (IM), or intradermal (ID) vaccination of mice, followed by challenge with a lethal dose of virus. In addition to all of the vaccinated animals surviving the lethal dose, significantly stronger early immune responses were observed (anti-viral activity via virus neutralization assay and HA inhibition (HAI)) in comparison to protein antigen and other lipid based formulations (lipoplex). The data demonstrated that as early as 1 week after vaccination both groups of animals receiving a chemically modified mRNA-LNP formulation (ID or IM) displayed HAI titers over 40, at 60 and 114, respectively. An HAI titer of greater than 40 is deemed sufficient to protect from a lethal challenge of influenza. The rapid response was unexpected, particularly when compared to the response seen with protein antigen and mRNA vaccines formulated in other lipid carriers (lipoplex), which at one week and even at three weeks following vaccination continued to show ineffective HAI titers of less than 40.

At each of the later time points (3 weeks and 5 weeks), the formulations of the invention continued to provide significantly stronger therapeutic responses than did protein antigen. In fact even chemically unmodified mRNA-LNP formulation administered by IV route had enhanced HAI titers with respect to the protein antigen. By week 3, all of the animals receiving an mRNA-LNP formulation by IM or ID administration displayed HAI activity over 40, as compared to protein antigen, which at one week and three weeks continued to show HAI titers of less than 40. By week 5 the chemically modified mRNA-LNP formulation administered by ID route had a surprising HAI activity of greater than 10,000, in contrast to the HAI titer of around 400 for protein antigen at that time point.

Both the chemically modified and unmodified RNA vaccines of the invention produced better immune responses than did mRNA vaccines formulated in a different lipid carrier (lipoplex). At week 5 the non-chemically modified mRNA-lipoplex vaccine produced HAI titers of 197, in comparison to those achieved by the mRNA-LNP formulations of the invention (HAI titers of 635-10,152). At all other time points and for all of the chemically modified mRNA-lipoplex vaccines, none of the HAI titers reached the critical level of greater than 40. Additionally, the mRNA-lipoplex vaccine did not result in any detectable neutralizing activity in the microneutralization activity, even as late as five weeks after vaccination.

As used herein in a polynucleotide (such as a chimeric polynucleotide, IVT polynucleotide or a circular polynucleotide), the terms “chemical modification” or, as appropriate, “chemically modified” refer to modification with respect to adenosine (A), guanosine (G), uridine (U), thymidine (T) or cytidine (C) ribo- or deoxyribnucleosides in one or more of their position, pattern, percent or population. Generally, herein, these terms are not intended to refer to the ribonucleotide modifications in naturally occurring 5′-terminal mRNA cap moieties.

In a polypeptide, the term “modification” refers to a modification as compared to the canonical set of 20 amino acids.

The modifications may be various distinct modifications. In some embodiments, the regions may contain one, two, or more (optionally different) nucleoside or nucleotide modifications. In some embodiments, a modified polynucleotide, introduced to a cell may exhibit reduced degradation in the cell, as compared to an unmodified polynucleotide.

Modifications of the polynucleotides of the NAVs which are useful in the present invention include, but are not limted to those in Table 22. Noted in the table are the symbol of the modification, the nucleobase type and whether the modification is naturally occurring or not.

TABLE 22 Modifications Naturally Name Symbol Base Occurring 2-methylthio-N6-(cis- ms2i6A A YES hydroxyisopentenyl)adenosine 2-methylthio-N6-methyladenosine ms2m6A A YES 2-methy1lthio-N6-threonyl ms2t6A A YES carbamoyladenosine N6-glycinylcarbamoyladenosine g6A A YES N6-isopentenyladenosine i6A A YES N6-methyladenosine m6A A YES N6-threonylcarbamoyladenosine t6A A YES 1,2′-O-dimethyladenosine m1Am A YES 1-methyladenosine m1A A YES 2′-O-methyladenosine Am A YES 2′-O-ribosyladenosine (phosphate) Ar(p) A YES 2-methyladenosine m2A A YES 2-methylthio-N6 isopentenyladenosine ms2i6A A YES 2-methylthio-N6-hydroxynorvalyl ms2hn6A A YES carbamoyladenosine 2′-O-methyladenosine m6A A YES 2′-O-ribosyladenosine (phosphate) Ar(p) A YES Isopentenyladenosine Iga A YES N6-(cis-hydroxyisopentenyl)adenosine io6A A YES N6,2′-O-dimethyladenosine m6Am A YES N⁶,2′-O-dimethyladenosine m⁶Am A YES N6,N6,2′-O-trimethyladenosine m62Am A YES N6,N6-dimethyladenosine m62A A YES N6-acetyladenosine ac6A A YES N6-hydroxynorvalylcarbamoyladenosine hn6A A YES N6-methyl-N6- m6t6A A YES threonylcarbamoyladenosine 2-methyladenosine m²A A YES 2-methylthio-N⁶-isopentenyladenosine ms²i⁶A A YES 7-deaza-adenosine — A NO N1-methyl-adenosine — A NO N6,N6 (dimethyl)adenine — A NO N6-cis-hydroxy-isopentenyl-adenosine — A NO α-thio-adenosine — A NO 2 (amino)adenine — A NO 2 (aminopropyl)adenine — A NO 2 (methylthio) N6 (isopentenyl)adenine — A NO 2-(alkyl)adenine — A NO 2-(aminoalkyl)adenine — A NO 2-(aminopropyl)adenine — A NO 2-(halo)adenine — A NO 2-(halo)adenine — A NO 2-(propyl)adenine — A NO 2′-Amino-2′-deoxy-ATP — A NO 2′-Azido-2′-deoxy-ATP — A NO 2′-Deoxy-2′-a-aminoadenosine TP — A NO 2′-Deoxy-2′-a-azidoadenosine TP — A NO 6 (alkyl)adenine — A NO 6 (methyl)adenine — A NO 6-(alkyl)adenine — A NO 6-(methyl)adenine — A NO 7 (deaza)adenine — A NO 8 (alkenyl)adenine — A NO 8 (alkynyl)adenine — A NO 8 (amino)adenine — A NO 8 (thioalkyl)adenine — A NO 8-(alkenyl)adenine — A NO 8-(alkyl)adenine — A NO 8-(alkynyl)adenine — A NO 8-(amino)adenine — A NO 8-(halo)adenine — A NO 8-(hydroxyl)adenine — A NO 8-(thioalkyl)adenine — A NO 8-(thiol)adenine — A NO 8-azido-adenosine — A NO aza adenine — A NO deaza adenine — A NO N6 (methyl)adenine — A NO N6-(isopentyl)adenine — A NO 7-deaza-8-aza-adenosine — A NO 7-methyladenine — A NO 1-Deazaadenosine TP — A NO 2′Fluoro-N6-Bz-deoxyadenosine TP — A NO 2′-OMe-2-Amino-ATP — A NO 2′O-methyl-N6-Bz-deoxyadenosine TP — A NO 2′-a-Ethynyladenosine TP — A NO 2-aminoadenine — A NO 2-Aminoadenosine TP — A NO 2-Amino-ATP — A NO 2′-a-Trifluoromethyladenosine TP — A NO 2-Azidoadenosine TP — A NO 2′-b-Ethynyladenosine TP — A NO 2-Bromoadenosine TP — A NO 2′-b-Trifluoromethyladenosine TP — A NO 2-Chloroadenosine TP — A NO 2′-Deoxy-2′,2′-difluoroadenosine TP — A NO 2′-Deoxy-2′-a-mercaptoadenosine TP — A NO 2′-Deoxy-2′-a-thiomethoxyadenosine TP — A NO 2′-Deoxy-2′-b-aminoadenosine TP — A NO 2′-Deoxy-2′-b-azidoadenosine TP — A NO 2′-Deoxy-2′-b-bromoadenosine TP — A NO 2′-Deoxy-2′-b-chloroadenosine TP — A NO 2′-Deoxy-2′-b-fluoroadenosine TP — A NO 2′-Deoxy-2′-b-iodoadenosine TP — A NO 2′-Deoxy-2′-b-mercaptoadenosine TP — A NO 2′-Deoxy-2′-b-thiomethoxyadenosine TP — A NO 2-Fluoroadenosine TP — A NO 2-Iodoadenosine TP — A NO 2-Mercaptoadenosine TP — A NO 2-methoxy-adenine — A NO 2-methylthio-adenine — A NO 2-Trifluoromethyladenosine TP — A NO 3-Deaza-3-bromoadenosine TP — A NO 3-Deaza-3-chloroadenosine TP — A NO 3-Deaza-3-fluoroadenosine TP — A NO 3-Deaza-3-iodoadenosine TP — A NO 3-Deazaadenosine TP — A NO 4′-Azidoadenosine TP — A NO 4′-Carbocyclic adenosine TP — A NO 4′-Ethynyladenosine TP — A NO 5′-Homo-adenosine TP — A NO 8-Aza-ATP — A NO 8-bromo-adenosine TP — A NO 8-Trifluoromethyladenosine TP — A NO 9-Deazaadenosine TP — A NO 2-aminopurine — A/G NO 7-deaza-2,6-diaminopurine — A/G NO 7-deaza-8-aza-2,6-diaminopurine — A/G NO 7-deaza-8-aza-2-aminopurine — A/G NO 2,6-diaminopurine — A/G NO 7-deaza-8-aza-adenine, — A/G NO 7-deaza-2-aminopurine 2-thiocytidine s2C C YES 3-methylcytidine m3C C YES 5-formylcytidine f5C C YES 5-hydroxymethylcytidine hm5C C YES 5-methylcytidine m5C C YES N4-acetylcytidine ac4C C YES 2′-O-methylcytidine Cm C YES 2′-O-methylcytidine Cm C YES 5,2′-O-dimethylcytidine m5 Cm C YES 5-formyl-2′-O-methylcytidine f5Cm C YES Lysidine k2C C YES N4,2′-O-dimethylcytidine m4Cm C YES N4-acetyl-2′-O-methylcytidine ac4Cm C YES N4-methylcytidine m4C C YES N4,N4-Dimethyl-2′-OMe-Cytidine TP — C YES 4-methylcytidine — C NO 5-aza-cytidine — C NO Pseudo-iso-cytidine — C NO pyrrolo-cytidine — C NO α-thio-cytidine — C NO 2-(thio)cytosine — C NO 2′-Amino-2′-deoxy-CTP — C NO 2′-Azido-2′-deoxy-CTP — C NO 2′-Deoxy-2′-a-aminocytidine TP — C NO 2′-Deoxy-2′-a-azidocytidine TP — C NO 3 (deaza) 5 (aza)cytosine — C NO 3 (methyl)cytosine — C NO 3-(alkyl)cytosine — C NO 3-(deaza) 5 (aza)cytosine — C NO 3-(methyl)cytidine — C NO 4,2′-O-dimethylcytidine — C NO 5 (halo)cytosine — C NO 5 (methyl)cytosine — C NO 5 (propynyl)cytosine — C NO 5 (trifluoromethyl)cytosine — C NO 5-(alkyl)cytosine — C NO 5-(alkynyl)cytosine — C NO 5-(halo)cytosine — C NO 5-(propynyl)cytosine — C NO 5-(trifluoromethyl)cytosine — C NO 5-bromo-cytidine — C NO 5-iodo-cytidine — C NO 5-propynyl cytosine — C NO 6-(azo)cytosine — C NO 6-aza-cytidine — C NO aza cytosine — C NO deaza cytosine — C NO N4 (acetyl)cytosine — C NO 1-methyl-1-deaza-pseudoisocytidine — C NO 1-methyl-pseudoisocytidine — C NO 2-methoxy-5-methyl-cytidine — C NO 2-methoxy-cytidine — C NO 2-thio-5-methyl-cytidine — C NO 4-methoxy-1-methyl-pseudoisocytidine — C NO 4-methoxy-pseudoisocytidine — C NO 4-thio-1-methyl-1-deaza-pseudoisocytidine — C NO 4-thio-1-methyl-pseudoisocytidine — C NO 4-thio-pseudoisocytidine — C NO 5-aza-zebularine — C NO 5-methyl-zebularine — C NO pyrrolo-pseudoisocytidine — C NO Zebularine — C NO (E)-5-(2-Bromo-vinyl)cytidine TP — C NO 2,2′-anhydro-cytidine TP hydrochloride — C NO 2′Fluor-N4-Bz-cytidine TP — C NO 2′Fluoro-N4-Acetyl-cytidine TP — C NO 2′-O-Methyl-N4-Acetyl-cytidine TP — C NO 2′O-methyl-N4-Bz-cytidine TP — C NO 2′-a-Ethynylcytidine TP — C NO 2′-a-Trifluoromethylcytidine TP — C NO 2′-b-Ethynylcytidine TP — C NO 2′-b-Trifluoromethylcytidine TP — C NO 2′-Deoxy-2′,2′-difluorocytidine TP — C NO 2′-Deoxy-2′-a-mercaptocytidine TP — C NO 2′-Deoxy-2′-a-thiomethoxycytidine TP — C NO 2′-Deoxy-2′-b-aminocytidine TP — C NO 2′-Deoxy-2′-b-azidocytidine TP — C NO 2′-Deoxy-2′-b-bromocytidine TP — C NO 2′-Deoxy-2′-b-chlorocytidine TP — C NO 2′-Deoxy-2′-b-fluorocytidine TP — C NO 2′-Deoxy-2′-b-iodocytidine TP — C NO 2′-Deoxy-2′-b-mercaptocytidine TP — C NO 2′-Deoxy-2′-b-thiomethoxycytidine TP — C NO 2′-O-Methyl-5-(1-propynyl)cytidine TP — C NO 3′-Ethynylcytidine TP — C NO 4′-Azidocytidine TP — C NO 4′-Carbocyclic cytidine TP — C NO 4′-Ethynylcytidine TP — C NO 5-(1-Propynyl)ara-cytidine TP — C NO 5-(2-Chloro-phenyl)-2-thiocytidine TP — C NO 5-(4-Amino-phenyl)-2-thiocytidine TP — C NO 5-Aminoallyl-CTP — C NO 5-Cyanocytidine TP — C NO 5-Ethynylara-cytidine TP — C NO 5-Ethynylcytidine TP — C NO 5′-Homo-cytidine TP — C NO 5-Methoxycytidine TP — C NO 5-Trifluoromethyl-Cytidine TP — C NO N4-Amino-cytidine TP — C NO N4-Benzoyl-cytidine TP — C NO Pseudoisocytidine — C NO 7-methylguanosine m7G G YES N2,2′-O-dimethylguanosine m2Gm G YES N2-methylguanosine m2G G YES Wyosine imG G YES 1,2′-O-dimethylguanosine m1Gm G YES 1-methylguanosine m1G G YES 2′-O-methylguanosine Gm G YES 2′-O-ribosylguanosine (phosphate) Gr(p) G YES 2′-O-methylguanosine Gm G YES 2′-O-ribosylguanosine (phosphate) Gr(p) G YES 7-aminomethyl-7-deazaguanosine preQ1 G YES 7-cyano-7-deazaguanosine preQ0 G YES Archaeosine G+ G YES Methylwyosine mimG G YES N2,7-dimethylguanosine m2,7G G YES N2,N2,2′-O-trimethylguanosine m22Gm G YES N2,N2,7-trimethylguanosine m2,2,7G G YES N2,N2-dimethylguanosine m22G G YES N²,7,2′-O-trimethylguanosine m^(2,7)Gm G YES 6-thio-guanosine — G NO 7-deaza-guanosine — G NO 8-oxo-guanosine — G NO N1-methyl-guanosine — G NO α-thio-guanosine — G NO 2 (propyl)guanine — G NO 2-(alkyl)guanine — G NO 2′-Amino-2′-deoxy-GTP — G NO 2′-Azido-2′-deoxy-GTP — G NO 2′-Deoxy-2′-a-aminoguanosine TP — G NO 2′-Deoxy-2′-a-azidoguanosine TP — G NO 6 (methyl)guanine — G NO 6-(alkyl)guanine — G NO 6-(methyl)guanine — G NO 6-methyl-guanosine — G NO 7 (alkyl)guanine — G NO 7 (deaza)guanine — G NO 7 (methyl)guanine — G NO 7-(alkyl)guanine — G NO 7-(deaza)guanine — G NO 7-(methyl)guanine — G NO 8 (alkyl)guanine — G NO 8 (alkynyl)guanine — G NO 8 (halo)guanine — G NO 8 (thioalkyl)guanine — G NO 8-(alkenyl)guanine — G NO 8-(alkyl)guanine — G NO 8-(alkynyl)guanine — G NO 8-(amino)guanine — G NO 8-(halo)guanine — G NO 8-(hydroxyl)guanine — G NO 8-(thioalkyl)guanine — G NO 8-(thiol)guanine — G NO aza guanine — G NO deaza guanine — G NO N (methyl)guanine — G NO N-(methyl)guanine — G NO 1-methyl-6-thio-guanosine — G NO 6-methoxy-guanosine — G NO 6-thio-7-deaza-8-aza-guanosine — G NO 6-thio-7-deaza-guanosine — G NO 6-thio-7-methyl-guanosine — G NO 7-deaza-8-aza-guanosine — G NO 7-methyl-8-oxo-guanosine — G NO N2,N2-dimethyl-6-thio-guanosine — G NO N2-methyl-6-thio-guanosine — G NO 1-Me-GTP — G NO 2′Fluoro-N2-isobutyl-guanosine TP — G NO 2′O-methyl-N2-isobutyl-guanosine TP — G NO 2′-a-Ethynylguanosine TP — G NO 2′-a-Trifluoromethylguanosine TP — G NO 2′-b-Ethynylguanosine TP — G NO 2′-b-Trifluoromethylguanosine TP — G NO 2′-Deoxy-2′,2′-difluoroguanosine TP — G NO 2′-Deoxy-2′-a-mercaptoguanosine TP — G NO 2′-Deoxy-2′-a-thiomethoxyguanosine TP — G NO 2′-Deoxy-2′-b-aminoguanosine TP — G NO 2′-Deoxy-2′-b-azidoguanosine TP — G NO 2′-Deoxy-2′-b-bromoguanosine TP — G NO 2′-Deoxy-2′-b-chloroguanosine TP — G NO 2′-Deoxy-2′-b-fluoroguanosine TP — G NO 2′-Deoxy-2′-b-iodoguanosine TP — G NO 2′-Deoxy-2′-b-mercaptoguanosine TP — G NO 2′-Deoxy-2′-b-thiomethoxyguanosine TP — G NO 4′-Azidoguanosine TP — G NO 4′-Carbocyclic guanosine TP — G NO 4′-Ethynylguanosine TP — G NO 5′-Homo-guanosine TP — G NO 8-bromo-guanosine TP — G NO 9-Deazaguanosine TP — G NO N2-isobutyl-guanosine TP — G NO 1-methylinosine m1I I YES Inosine I I YES 1,2′-O-dimethylinosine m1Im I YES 2′-O-methylinosine Im I YES 7-methylinosine I NO 2′-O-methylinosine Im I YES Epoxyqueuosine oQ Q YES galactosyl-queuosine galQ Q YES Mannosylqueuosine manQ Q YES Queuosine Q Q YES allyamino-thymidine — T NO aza thymidine — T NO deaza thymidine — T NO deoxy-thymidine — T NO 2′-O-methyluridine — U YES 2-thiouridine s2U U YES 3-methyluridine m3U U YES 5-carboxymethyluridine cm5U U YES 5-hydroxyuridine ho5U U YES 5-methyluridine m5U U YES 5-taurinomethyl-2-thiouridine τm5s2U U YES 5-taurinomethyluridine τm5U U YES Dihydrouridine D U YES Pseudouridine Ψ U YES (3-(3-amino-3-carboxypropyl)uridine acp3U U YES 1-methyl-3-(3-amino-5- m1acp3Ψ U YES carboxypropyl)pseudouridine 1-methylpseduouridine m1Ψ U YES 1-methyl-pseudouridine — U YES 2′-O-methyluridine Um U YES 2′-O-methylpseudouridine Ψm U YES 2′-O-methyluridine Um U YES 2-thio-2′-O-methyluridine s2Um U YES 3-(3-amino-3-carboxypropyl)uridine acp3U U YES 3,2′-O-dimethyluridine m3Um U YES 3-Methyl-pseudo-Uridine TP — U YES 4-thiouridine s4U U YES 5-(carboxyhydroxymethyl)uridine chm5U U YES 5-(carboxyhydroxymethyl)uridine methyl mchm5U U YES ester 5,2′-O-dimethyluridine m5Um U YES 5,6-dihydro-uridine — U YES 5-aminomethyl-2-thiouridine nm5s2U U YES 5-carbamoylmethyl-2′-O-methyluridine ncm5Um U YES 5-carbamoylmethyluridine ncm5U U YES 5-carboxyhydroxymethyluridine — U YES 5-carboxyhydroxymethyluridine methyl — U YES ester 5-carboxymethylaminomethyl-2′-O- cmnm5Um U YES methyluridine 5-carboxymethylaminomethyl-2- cmnm5s2U U YES thiouridine 5-carboxymethylaminomethyl-2- — U YES thiouridine 5-carboxymethylaminomethyluridine cmnm5U U YES 5-carboxymethylaminomethyluridine — U YES 5-Carbamoylmethyluridine TP — U YES 5-methoxycarbonylmethyl-2′-O- mcm5Um U YES methyluridine 5-methoxycarbonylmethyl-2-thiouridine mcm5s2U U YES 5-methoxycarbonylmethyluridine mcm5U U YES 5-methoxyuridine mo5U U YES 5-methyl-2-thiouridine m5s2U U YES 5-methylaminomethyl-2-selenouridine mnm5se2U U YES 5-methylaminomethyl-2-thiouridine mnm5s2U U YES 5-methylaminomethyluridine mnm5U U YES 5-Methyldihydrouridine — U YES 5-Oxyacetic acid-Uridine TP — U YES 5-Oxyacetic acid-methyl ester-Uridine TP — U YES N1-methyl-pseudo-uridine — U YES uridine 5-oxyacetic acid cmo5U U YES uridine 5-oxyacetic acid methyl ester mcmo5U U YES 3-(3-Amino-3-carboxypropyl)-Uridine TP — U YES 5-(iso-Pentenylaminomethyl)-2- — U YES thiouridine TP 5-(iso-Pentenylaminomethyl)-2′-O- — U YES methyluridine TP 5-(iso-Pentenylaminomethyl)uridine TP — U YES 5-propynyl uracil — U NO α-thio-uridine — U NO 1 (aminoalkylamino-carbonylethylenyl)- — U NO 2(thio)-pseudouracil 1 (aminoalkylaminocarbonylethylenyl)- — U NO 2,4-(dithio)pseudouracil 1 (aminoalkylaminocarbonylethylenyl)- — U NO 4(thio)pseudouracil 1 (aminoalkylaminocarbonylethylenyl)- — U NO pseudouracil 1 (aminocarbonylethylenyl)-2(thio)- — U NO pseudouracil 1 (aminocarbonylethylenyl)-2,4- — U NO (dithio)pseudouracil 1 (aminocarbonylethylenyl)- — U NO 4(thio)pseudouracil 1 (aminocarbonylethylenyl)-pseudouracil — U NO 1 substituted 2(thio)-pseudouracil — U NO 1 substituted 2,4-(dithio)pseudouracil — U NO 1 substituted 4 (thio)pseudouracil — U NO 1 substituted pseudouracil — U NO 1-(aminoalkylamino-carbonylethylenyl)-2- — U NO (thio)-pseudouracil 1-Methyl-3-(3-amino-3- — U NO carboxypropyl) pseudouridine TP 1-Methyl-3-(3-amino-3- — U NO carboxypropyl)pseudo-UTP 1-Methyl-pseudo-UTP — U NO 2 (thio)pseudouracil — U NO 2′ deoxy uridine — U NO 2′ fluorouridine — U NO 2-(thio)uracil — U NO 2,4-(dithio)psuedouracil — U NO 2′ methyl, 2′amino, 2′azido, 2′fluro- — U NO guanosine 2′-Amino-2′-deoxy-UTP — U NO 2′-Azido-2′-deoxy-UTP — U NO 2′-Azido-deoxyuridine TP — U NO 2′-O-methylpseudouridine — U NO 2′ deoxy uridine 2′ dU U NO 2′ fluorouridine — U NO 2′-Deoxy-2′-a-aminouridine TP — U NO 2′-Deoxy-2′-a-azidouridine TP — U NO 2-methylpseudouridine m3Ψ U NO 3 (3 amino-3 carboxypropyl)uracil — U NO 4 (thio)pseudouracil — U NO 4-(thio)pseudouracil — U NO 4-(thio)uracil — U NO 4-thiouracil — U NO 5 (1,3-diazole-1-alkyl)uracil — U NO 5 (2-aminopropyl)uracil — U NO 5 (aminoalkyl)uracil — U NO 5 (dimethylaminoalkyl)uracil — U NO 5 (guanidiniumalkyl)uracil — U NO 5 (methoxycarbonylmethyl)-2-(thio)uracil — U NO 5 (methoxycarbonyl-methyl)uracil — U NO 5 (methyl) 2 (thio)uracil — U NO 5 (methyl) 2,4 (dithio)uracil — U NO 5 (methyl) 4 (thio)uracil — U NO 5 (methylaminomethyl)-2 (thio)uracil — U NO 5 (methylaminomethyl)-2,4 (dithio)uracil — U NO 5 (methylaminomethyl)-4 (thio)uracil — U NO 5 (propynyl)uracil — U NO 5 (trifluoromethyl)uracil — U NO 5-(2-aminopropyl)uracil — U NO 5-(alkyl)-2-(thio)pseudouracil — U NO 5-(alkyl)-2,4 (dithio)pseudouracil — U NO 5-(alkyl)-4 (thio)pseudouracil — U NO 5-(alkyl)pseudouracil — U NO 5-(alkyl)uracil — U NO 5-(alkynyl)uracil — U NO 5-(allylamino)uracil — U NO 5-(cyanoalkyl)uracil — U NO 5-(dialkylaminoalkyl)uracil — U NO 5-(dimethylaminoalkyl)uracil — U NO 5-(guanidiniumalkyl)uracil — U NO 5-(halo)uracil — U NO 5-(l,3-diazole-l-alkyl)uracil — U NO 5-(methoxy)uracil — U NO 5-(methoxycarbonylmethyl)-2-(thio)uracil — U NO 5-(methoxycarbonyl-methyl)uracil — U NO 5-(methyl) 2(thio)uracil — U NO 5-(methyl) 2,4 (dithio)uracil — U NO 5-(methyl) 4 (thio)uracil — U NO 5-(methyl)-2-(thio)pseudouracil — U NO 5-(methyl)-2,4 (dithio)pseudouracil — U NO 5-(methyl)-4 (thio)pseudouracil — U NO 5-(methyl)pseudouracil — U NO 5-(methylaminomethyl)-2 (thio)uracil — U NO 5-(methylaminomethyl)-2,4(dithio)uracil — U NO 5-(methylaminomethyl)-4-(thio)uracil — U NO 5-(propynyl)uracil — U NO 5-(trifluoromethyl)uracil — U NO 5-aminoallyl-uridine — U NO 5-bromo-uridine — U NO 5-iodo-uridine — U NO 5-uracil — U NO 6 (azo)uracil — U NO 6-(azo)uracil — U NO 6-aza-uridine — U NO allyamino-uracil — U NO aza uracil — U NO deaza uracil — U NO N3 (methyl)uracil — U NO Pseudo-UTP-1-2-ethanoic acid — U NO Pseudouracil — U NO 4-Thio-pseudo-UTP — U NO 1-carboxymethyl-pseudouridine — U NO 1-methyl-1-deaza-pseudouridine — U NO 1-propynyl-uridine — U NO 1-taurinomethyl-1-methyl-uridine — U NO 1-taurinomethyl-4-thio-uridine — U NO 1-taurinomethyl-pseudouridine — U NO 2-methoxy-4-thio-pseudouridine — U NO 2-thio-1-methyl-1-deaza-pseudouridine — U NO 2-thio-1-methyl-pseudouridine — U NO 2-thio-5-aza-uridine — U NO 2-thio-dihydropseudouridine — U NO 2-thio-dihydrouridine — U NO 2-thio-pseudouridine — U NO 4-methoxy-2-thio-pseudouridine — U NO 4-methoxy-pseudouridine — U NO 4-thio-1-methyl-pseudouridine — U NO 4-thio-pseudouridine — U NO 5-aza-uridine — U NO Dihydropseudouridine — U NO (±)1-(2-Hydroxypropyl)pseudouridine TP — U NO (2R)-1-(2-Hydroxypropyl)pseudouridine TP — U NO (2S)-1-(2-Hydroxypropyl)pseudouridine TP — U NO (E)-5-(2-Bromo-vinyl)ara-uridine TP — U NO (E)-5-(2-Bromo-vinyl)uridine TP — U NO (Z)-5-(2-Bromo-vinyl)ara-uridine TP — U NO (Z)-5-(2-Bromo-vinyl)uridine TP — U NO 1-(2,2,2-Trifluoroethyl)-pseudo-UTP — U NO 1-(2,2,3,3,3- — U NO Pentafluoropropyl)pseudouridine TP 1-(2,2-Diethoxyethyl)pseudouridine TP — U NO 1-(2,4,6-Trimethylbenzyl)pseudouridine TP — U NO 1-(2,4,6-Trimethyl-benzyl)pseudo-UTP — U NO 1-(2,4,6-Trimethyl-phenyl)pseudo-UTP — U NO 1-(2-Amino-2-carboxyethyl)pseudo-UTP — U NO 1-(2-Amino-ethyl)pseudo-UTP — U NO 1-(2-Hydroxyethyl)pseudouridine TP — U NO 1-(2-Methoxyethyl)pseudouridine TP — U NO 1-(3,4-Bis- — U NO trifluoromethoxybenzyl)pseudouridine TP 1-(3,4-Dimethoxybenzyl)pseudouridine TP — U NO 1-(3-Amino-3-carboxypropyl)pseudo-UTP — U NO 1-(3-Amino-propyl)pseudo-UTP — U NO 1-(3-Cyclopropyl-prop-2- — U NO ynyl)pseudouridine TP 1-(4-Amino-4-carboxybutyl)pseudo-UTP — U NO 1-(4-Amino-benzyl)pseudo-UTP — U NO 1-(4-Amino-butyl)pseudo-UTP — U NO 1-(4-Amino-phenyl)pseudo-UTP — U NO 1-(4-Azidobenzyl)pseudouridine TP — U NO 1-(4-Bromobenzyl)pseudouridine TP — U NO 1-(4-Chlorobenzyl)pseudouridine TP — U NO 1-(4-Fluorobenzyl)pseudouridine TP — U NO 1-(4-Iodobenzyl)pseudouridine TP — U NO 1-(4- — U NO Methanesulfonylbenzyl)pseudouridine TP 1-(4-Methoxybenzyl)pseudouridine TP — U NO 1-(4-Methoxy-benzyl)pseudo-UTP — U NO 1-(4-Methoxy-phenyl)pseudo-UTP — U NO 1-(4-Methylbenzyl)pseudouridine TP — U NO 1-(4-Methyl-benzyl)pseudo-UTP — U NO 1-(4-Nitrobenzyl)pseudouridine TP — U NO 1-(4-Nitro-benzyl)pseudo-UTP — U NO 1(4-Nitro-phenyl)pseudo-UTP — U NO 1-(4-Thiomethoxybenzyl)pseudouridine TP — U NO 1-(4- — U NO Trifluoromethoxybenzyl)pseudouridine TP 1-(4-Trifluoromethylbenzyl)pseudouridine TP — U NO 1-(5-Amino-pentyl)pseudo-UTP — U NO 1-(6-Amino-hexyl)pseudo-UTP — U NO 1,6-Dimethyl-pseudo-UTP — U NO 1-[3-(2-{2-[2-(2-Aminoethoxy)-ethoxy]- — U NO ethoxy}-ethoxy)-propionyl]pseudouridine TP 1-{3-[2-(2-Aminoethoxy)-ethoxy]- — U NO propionyl} pseudouridine TP 1-Acetylpseudouridine TP — U NO 1-Alkyl-6-(1-propynyl)-pseudo-UTP — U NO 1-Alkyl-6-(2-propynyl)-pseudo-UTP — U NO 1-Alkyl-6-allyl-pseudo-UTP — U NO 1-Alkyl-6-ethynyl-pseudo-UTP — U NO 1-Alkyl-6-homoallyl-pseudo-UTP — U NO 1-Alkyl-6-vinyl-pseudo-UTP — U NO 1-Allylpseudouridine TP — U NO 1-Aminomethyl-pseudo-UTP — U NO 1-Benzoylpseudouridine TP — U NO 1-Benzyloxymethylpseudouridine TP — U NO 1-Benzyl-pseudo-UTP — U NO 1-Biotinyl-PEG2-pseudouridine TP — U NO 1-Biotinylpseudouridine TP — U NO 1-Butyl-pseudo-UTP — U NO 1-Cyanomethylpseudouridine TP — U NO 1-Cyclobutylmethyl-pseudo-UTP — U NO 1-Cyclobutyl-pseudo-UTP — U NO 1-Cycloheptylmethyl-pseudo-UTP — U NO 1-Cycloheptyl-pseudo-UTP — U NO 1-Cyclohexylmethyl-pseudo-UTP — U NO 1-Cyclohexyl-pseudo-UTP — U NO 1-Cyclooctylmethyl-pseudo-UTP — U NO 1-Cyclooctyl-pseudo-UTP — U NO 1-Cyclopentylmethyl-pseudo-UTP — U NO 1-Cyclopentyl-pseudo-UTP — U NO 1-Cyclopropylmethyl-pseudo-UTP — U NO 1-Cyclopropyl-pseudo-UTP — U NO 1-Ethyl-pseudo-UTP — U NO 1-Hexyl-pseudo-UTP — U NO 1-Homoallylpseudouridine TP — U NO 1-Hydroxymethylpseudouridine TP — U NO 1-iso-propyl-pseudo-UTP — U NO 1-Me-2-thio-pseudo-UTP — U NO 1-Me-4-thio-pseudo-UTP — U NO 1-Me-alpha-thio-pseudo-UTP — U NO 1-Methanesulfonylmethylpseudouridine TP — U NO 1-Methoxymethylpseudouridine TP — U NO 1-Methyl-6-(2,2,2-Trifluoroethyl)pseudo-UTP — U NO 1-Methyl-6-(4-morpholino)-pseudo-UTP — U NO 1-Methyl-6-(4-thiomorpholino)-pseudo-UTP — U NO 1-Methyl-6-(substituted phenyl)pseudo-UTP — U NO 1-Methyl-6-amino-pseudo-UTP — U NO 1-Methyl-6-azido-pseudo-UTP — U NO 1-Methyl-6-bromo-pseudo-UTP — U NO 1-Methyl-6-butyl-pseudo-UTP — U NO 1-Methyl-6-chloro-pseudo-UTP — U NO 1-Methyl-6-cyano-pseudo-UTP — U NO 1-Methyl-6-dimethylamino-pseudo-UTP — U NO 1-Methyl-6-ethoxy-pseudo-UTP — U NO 1-Methyl-6-ethylcarboxylate-pseudo-UTP — U NO 1-Methyl-6-ethyl-pseudo-UTP — U NO 1-Methyl-6-fluoro-pseudo-UTP — U NO 1-Methyl-6-formyl-pseudo-UTP — U NO 1-Methyl-6-hydroxyamino-pseudo-UTP — U NO 1-Mcthyl-6-hydroxy-pseudo-UTP — U NO 1-Methyl-6-iodo-pseudo-UTP — U NO 1-Methyl-6-iso-propyl-pseudo-UTP — U NO 1-Methyl-6-methoxy-pseudo-UTP — U NO 1-Methyl-6-methylamino-pseudo-UTP — U NO 1-Methyl-6-phenyl-pseudo-UTP — U NO 1-Methyl-6-propyl-pseudo-UTP — U NO 1-Methyl-6-tert-butyl-pseudo-UTP — U NO 1-Methyl-6-trifluoromethoxy-pseudo-UTP — U NO 1-Methyl-6-trifluoromethyl-pseudo-UTP — U NO 1-Morpholinomethylpseudouridine TP — U NO 1-Pentyl-pseudo-UTP — U NO 1-Phenyl-pseudo-UTP — U NO 1-Pivaloylpseudouridine TP — U NO 1-Propargylpseudouridine TP — U NO 1-Propyl-pseudo-UTP — U NO 1-propynyl-pseudouridine — U NO 1-p-tolyl-pseudo-UTP — U NO 1-tert-Butyl-pseudo-UTP — U NO 1-Thiomethoxymethylpseudouridine TP — U NO 1-Thiomorpholinomethylpseudouridine TP — U NO 1-Trifluoroacetylpseudouridine TP — U NO 1-Trifluoromethyl-pseudo-UTP — U NO 1-Vinylpseudouridine TP — U NO 2,2′-anhydro-uridine TP — U NO 2′-bromo-deoxyuridine TP — U NO 2′-F-5-Methyl-2′-deoxy-UTP — U NO 2′-OMe-5-Me-UTP — U NO 2′-OMe-pseudo-UTP — U NO 2′-a-Ethynyluridine TP — U NO 2′-a-Trifluoromethyluridine TP — U NO 2′-b-Ethynyluridine TP — U NO 2′-b-Trifluoromethyluridine TP — U NO 2′-Deoxy-2′,2′-difluorouridine TP — U NO 2′-Deoxy-2′-a-mercaptouridine TP — U NO 2′-Deoxy-2′-a-thiomethoxyuridine TP — U NO 2′-Deoxy-2′-b-aminouridine TP — U NO 2′-Deoxy-2′-b-azidouridine TP — U NO 2′-Deoxy-2′-b-bromouridine TP — U NO 2′-Deoxy-2′-b-chlorouridine TP — U NO 2′-Deoxy-2′-b-fluorouridine TP — U NO 2′-Deoxy-2′-b-iodouridine TP — U NO 2′-Deoxy-2′-b-mercaptouridine TP — U NO 2′-Deoxy-2′-b-thiomethoxyuridine TP — U NO 2-methoxy-4-thio-uridine — U NO 2-methoxyuridine — U NO 2′-O-Methyl-5-(1-propynyl)uridine TP — U NO 3-Alkyl-pseudo-UTP — U NO 4′-Azidouridine TP — U NO 4′-Carbocyclic uridine TP — U NO 4′-Ethynyluridine TP — U NO 5-(1-Propynyl)ara-uridine TP — U NO 5-(2-Furanyl)uridine TP — U NO 5-Cyanouridine TP — U NO 5-Dimethylaminouridine TP — U NO 5′-Homo-uridine TP — U NO 5-iodo-2′-fluoro-deoxyuridine TP — U NO 5-Phenylethynyluridine TP — U NO 5-Trideuteromethyl-6-deuterouridine TP — U NO 5-Trifluoromethyl-Uridine TP — U NO 5-Vinylarauridine TP — U NO 6-(2,2,2-Trifluoroethyl)-pseudo-UTP — U NO 6-(4-Morpholino)-pseudo-UTP — U NO 6-(4-Thiomorpholino)-pseudo-UTP — U NO 6-(Substituted-Phenyl)-pseudo-UTP — U NO 6-Amino-pseudo-UTP — U NO 6-Azido-pseudo-UTP — U NO 6-Bromo-pseudo-UTP — U NO 6-Butyl-pseudo-UTP — U NO 6-Chloro-pseudo-UTP — U NO 6-Cyano-pseudo-UTP — U NO 6-Dimethylamino-pseudo-UTP — U NO 6-Ethoxy-pseudo-UTP — U NO 6-Ethylcarboxylate-pseudo-UTP — U NO 6-Ethyl-pseudo-UTP — U NO 6-Fluoro-pseudo-UTP — U NO 6-Formyl-pseudo-UTP — U NO 6-Hydroxyamino-pseudo-UTP — U NO 6-Hydroxy-pseudo-UTP — U NO 6-Iodo-pseudo-UTP — U NO 6-iso-Propyl-pseudo-UTP — U NO 6-Methoxy-pseudo-UTP — U NO 6-Methylamino-pseudo-UTP — U NO 6-Methyl-pseudo-UTP — U NO 6-Phenyl-pseudo-UTP — U NO 6-Phenyl-pseudo-UTP — U NO 6-Propyl-pseudo-UTP — U NO 6-tert-Butyl-pseudo-UTP — U NO 6-Trifluoromethoxy-pseudo-UTP — U NO 6-Trifluoromethyl-pseudo-UTP — U NO Alpha-thio-pseudo-UTP — U NO Pseudouridine 1-(4-methylbenzenesulfonic — U NO acid) TP Pseudouridine 1-(4-methylbenzoic acid) TP — U NO Pseudouridine TP 1-[3-(2- — U NO ethoxy)]propionic acid Pseudouridine TP 1-[3-{2-(2-[2-(2-ethoxy)- — U NO ethoxy]-ethoxy)-ethoxy}]propionic acid Pseudouridine TP 1-[3-{2-(2-[2-{2(2- — U NO ethoxy)-ethoxy}-ethoxy]-ethoxy)- ethoxy}]propionic acid Pseudouridine TP 1-[3-{2-(2-[2-ethoxy]- — U NO ethoxy)-ethoxy}]propionic acid Pseudouridine TP 1-[3-{2-(2-ethoxy)- — U NO ethoxy}] propionic acid Pseudouridine TP 1-methylphosphonic acid — U NO Pseudouridine TP 1-methylphosphonic acid — U NO diethyl ester Pseudo-UTP-N1-3-propionic acid — U NO Pseudo-UTP-N1-4-butanoic acid — U NO Pseudo-UTP-N1-5-pentanoic acid — U NO Pseudo-UTP-N1-6-hexanoic acid — U NO Pseudo-UTP-N1-7-heptanoic acid — U NO Pseudo-UTP-N1-methyl-p-benzoic acid — U NO Pseudo-UTP-N1-p-benzoic acid — U NO Wybutosine yW W YES Hydroxywybutosine OHyW W YES Isowyosine imG2 W YES Peroxywybutosine o2yW W YES undermodified hydroxywybutosine OHyW* W YES 4-demethylwyosine imG-14 W YES

Other modifications which may be useful in the polynucleotides of the NAVs of the present invention are listed in Table 23.

TABLE 23 Additional Modification types Name Type 2,6-(diamino)purine Other 1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl Other 1,3-(diaza)-2-(oxo)-phenthiazin-1-yl Other 1,3-(diaza)-2-(oxo)-phenoxazin-1-yl Other 1,3,5-(triaza)-2,6-(dioxa)-naphthalene Other 2 (amino)purine Other 2,4,5-(trimethyl)phenyl Other 2′methyl, 2′amino, 2′azido, 2′fluro-cytidine Other 2′methyl, 2′amino, 2′azido, 2′fluro-adenine Other 2′methyl, 2′amino, 2′azido, 2′fluro-uridine Other 2′-amino-2′-deoxyribose Other 2-amino-6-Chloro-purine Other 2-aza-inosinyl Other 2′-azido-2′-deoxyribose Other 2′fluoro-2′-deoxyribose Other 2′-fluoro-modified bases Other 2′-O-methyl-ribose Other 2-oxo-7-aminopyridopyrimidin-3-yl Other 2-oxo-pyridopyrimidine-3-yl Other 2-pyridinone Other 3 nitropyrrole Other 3-(methyl)-7-(propynyl)isocarbostyrilyl Other 3-(methyl)isocarbostyrilyl Other 4-(fluoro)-6-(methyl)benzimidazole Other 4-(methyl)benzimidazole Other 4-(methyl)indolyl Other 4,6-(dimethyl)indolyl Other 5 nitroindole Other 5 substituted pyrimidines Other 5-(methyl)isocarbostyrilyl Other 5-nitroindole Other 6-(aza)pyrimidine Other 6-(azo)thymine Other 6-(methyl)-7-(aza)indolyl Other 6-chloro-purine Other 6-phenyl-pyrrolo-pyrimidin-2-on-3-yl Other 7-(aminoalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenthiazin-l-yl Other 7-(aminoalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl Other 7-(aminoalkylhydroxy)-1,3-(diaza)-2-(oxo)-phenoxazin-1-yl Other 7-(aminoalkylhydroxy)-l,3-(diaza)-2-(oxo)-phenthiazin-l-yl Other 7-(aminoalkylhydroxy)-l,3-(diaza)-2-(oxo)-phenoxazin-l-yl Other 7-(aza)indolyl Other 7-(guanidiniumalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenoxazinl-yl Other 7-(guanidiniumalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenthiazin-l-yl Other 7-(guanidiniumalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl Other 7-(guanidiniumalkylhydroxy)-1,3-(diaza)-2-(oxo)-phenoxazin-1-yl Other 7-(guanidiniumalkyl-hydroxy)-l,3-(diaza)-2-(oxo)-phenthiazin-l-yl Other 7-(guanidiniumalkylhydroxy)-l,3-(diaza)-2-(oxo)-phenoxazin-l-yl Other 7-(propynyl)isocarbostyrilyl Other 7-(propynyl)isocarbostyrilyl, propynyl-7-(aza)indolyl Other 7-deaza-inosinyl Other 7-substituted 1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl Other 7-substituted 1,3-(diaza)-2-(oxo)-phenoxazin-1-yl Other 9-(methyl)-imidizopyridinyl Other Aminoindolyl Other Anthracenyl Other bis-ortho-(aminoalkylhydroxy)-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl Other bis-ortho-substituted-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl Other Difluorotolyl Other Hypoxanthine Other Imidizopyridinyl Other Inosinyl Other Isocarbostyrilyl Other Isoguanisine Other N2-substituted purines Other N6-methyl-2-amino-purine Other N6-substituted purines Other N-alkylated derivative Other Napthalenyl Other Nitrobenzimidazolyl Other Nitroimidazolyl Other Nitroindazolyl Other Nitropyrazolyl Other Nubularine Other O6-substituted purines Other O-alkylated derivative Other ortho-(aminoalkylhydroxy)-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl Other ortho-substituted-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl Other Oxoformycin TP Other para-(aminoalkylhydroxy)-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl Other para-substituted-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl Other Pentacenyl Other Phenanthracenyl Other Phenyl Other propynyl-7-(aza)indolyl Other Pyrenyl Other pyridopyrimidin-3-yl Other pyridopyrimidin-3-yl, 2-oxo-7-amino-pyridopyrimidin-3-yl Other pyrrolo-pyrimidin-2-on-3-yl Other Pyrrolopyrimidinyl Other Pyrrolopyrizinyl Other Stilbenzyl Other substituted 1,2,4-triazoles Other Tetracenyl Other Tubercidine Other Xanthine Other Xanthosine-5′-TP Other 2-thio-zebularine Other 5-aza-2-thio-zebularine Other 7-deaza-2-amino-purine Other pyridin-4-one ribonucleoside Other 2-Amino-riboside-TP Other Formycin A TP Other Formycin B TP Other Pyrrolosine TP Other 2′-OH-ara-adenosine TP Other 2′-OH-ara-cytidine TP Other 2′-OH-ara-uridine TP Other 2′-OH-ara-guanosine TP Other 5-(2-carbomethoxyvinyl)uridine TP Other N6-(19-Amino-pentaoxanonadecyl)adenosine TP Other

The polynucleotides of the NAVs can include any useful linker between the nucleosides. Such linkers, including backbone modifications are given in Table 24.

TABLE 24 Linker modifications Name TYPE 3′-alkylene phosphonates Linker 3′-amino phosphoramidate Linker alkene containing backbones Linker Aminoalkylphosphoramidates Linker Aminoalkylphosphotriesters Linker Boranophosphates Linker —CH2-0-N(CH3)—CH2— Linker —CH2—N(CH3)—N(CH3)—CH2— Linker —CH2—NH—CH2— Linker chiral phosphonates Linker chiral phosphorothioates Linker formacetyl and thioformacetyl backbones Linker methylene (methylimino) Linker methylene formacetyl and thioformacetyl backbones Linker methyleneimino and methylenehydrazino backbones Linker morpholino linkages Linker —N(CH3)—CH2—CH2— Linker oligonucleosides with heteroatom internucleoside linkage Linker Phosphinates Linker phosphoramidates Linker Phosphorodithioates Linker phosphorothioate internucleoside linkages Linker Phosphorothioates Linker Phosphotriesters Linker PNA Linker siloxane backbones Linker sulfamate backbones Linker sulfide sulfoxide and sulfone backbones Linker sulfonate and sulfonamide backbones Linker Thionoalkylphosphonates Linker Thionoalkylphosphotriesters Linker Thionophosphoramidates Linker

The polynucleotides of the NAVs of the invention can include any useful modification, such as to the sugar, the nucleobase, or the internucleoside linkage (e.g. to a linking phosphate/to a phosphodiester linkage/to the phosphodiester backbone). One or more atoms of a pyrimidine nucleobase may be replaced or substituted with optionally substituted amino, optionally substituted thiol, optionally substituted alkyl (e.g., methyl or ethyl), or halo (e.g., chloro or fluoro). In certain embodiments, modifications (e.g., one or more modifications) are present in each of the sugar and the internucleoside linkage. Modifications according to the present invention may be modifications of ribonucleic acids (RNAs) to deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs) or hybrids thereof). Additional modifications are described herein.

Non-natural modified nucleotides may be introduced to polynucleotides, e.g., of the NAVs of the invention, or nucleic acids during synthesis or post-synthesis of the chains to achieve desired functions or properties. The modifications may be on internucleotide lineage, the purine or pyrimidine bases, or sugar. The modification may be introduced at the terminal of a chain or anywhere else in the chain; with chemical synthesis or with a polymerase enzyme. For example, hexitol nucleic acids (HNAs) are nuclease resistant and provide strong hybridization to RNA. Short messenger RNAs (mRNAs) with hexitol residues in two codons have been constructed (Lavrik et al., Biochemistry, 40, 11777-11784 (2001), the contents of which are incorporated herein by reference in their entirety). The antisense effects of a chimeric HNA gapmer oligonucleotide comprising a phosphorothioate central sequence flanked by 5′ and 3′ HNA sequences have also been studied (See e.g., Kang et al., Nucleic Acids Research, vol. 32(4), 4411-4419 (2004), the contents of which are incorporated herein by reference in their entirety). The preparation and uses of modified nucleotides comprising 6-member rings in RNA interference, antisense therapy or other applications are disclosed in US Pat. Application No. 2008/0261905, US Pat. Application No. 2010/0009865, and PCT Application No. WO97/30064 to Herdewijn et al.; the contents of each of which are herein incorporated by reference in their entireties). Modified nucleic acids and their synthesis are disclosed in copending PCT applications No. PCT/US2012/058519, the contents of which are incorporated herein by reference for their entirety. The synthesis and strategy of modified polynucleotides is reviewed by Verma and Eckstein in Annual Review of Biochemistry, vol. 76, 99-134 (1998), the contents of which are incorporated herein by reference in their entirety.

Either enzymatic or chemical ligation methods can be used to conjugate polynucleotides or their regions with different functional blocks, such as fluorescent labels, liquids, nanoparticles, delivery agents, etc. The conjugates of polynucleotides and modified polynucleotides are reviewed by Goodchild in Bioconjugate Chemistry, vol. 1(3), 165-187 (1990), the contents of which are incorporated herein by reference in their entirety. U.S. Pat. Nos. 6,835,827 and 6,525,183 to Vinayak et al. (the contents of each of which are herein incorporated by reference in their entireties) teach synthesis of labeled oligonucleotides using a labeled solid support.

In certain embodiments, it may desirable to intracellularly degrade a polynulcleotide introduced into the cell. For example, degradation of a polynulcleotide may be preferable if precise timing of protein production is desired. Thus, in some embodiments, the invention provides a polynulcleotide containing a degradation domain, which is capable of being acted on in a directed manner within a cell.

Any of the regions of the polynucleotides may be chemically modified as taught herein or as taught in International Application Number PCT/2012/058519 filed Oct. 3, 2012 and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 the contents of each of which are incorporated herein by reference in its entirety.

Modified Polynucleotide Molecules

The present invention also includes building blocks, e.g., modified ribonucleosides, and modified ribonucleotides, of polynucleotide molecules, e.g., of the NAVs of the invention. For example, these building blocks can be useful for preparing the polynucleotides of the invention. Such building blocks are taught in

International Application Number PCT/2012/058519 filed Oct. 3, 2012 and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 the contents of each of which are incorporated herein by reference in its entirety.

Modifications on the Sugar

The modified nucleosides and nucleotides (e.g., building block molecules), which may be incorporated into a polynucleotide (e.g., RNA or mRNA, as described herein), can be modified on the sugar of the ribonucleic acid. For example, the 2′ hydroxyl group (OH) can be modified or replaced with a number of different substituents. Exemplary substitutions at the 2′-position include, but are not limited to, H, halo, optionally substituted C₁₋₆ alkyl; optionally substituted C₁₋₆ alkoxy; optionally substituted C₆₋₁₀ aryloxy; optionally substituted C₃₋₈ cycloalkyl; optionally substituted C₃₋₈ cycloalkoxy; optionally substituted C₆₋₁₀ aryloxy; optionally substituted C₆₋₁₀ aryl-C₁₋₆ alkoxy, optionally substituted C₁₋₁₂ (heterocyclyl)oxy; a sugar (e.g., ribose, pentose, or any described herein); a polyethyleneglycol (PEG), —O(CH₂CH₂O)_(n)CH₂CH₂OR, where R is H or optionally substituted alkyl, and n is an integer from 0 to 20 (e.g., from 0 to 4, from 0 to 8, from 0 to 10, from 0 to 16, from 1 to 4, from 1 to 8, from 1 to 10, from 1 to 16, from 1 to 20, from 2 to 4, from 2 to 8, from 2 to 10, from 2 to 16, from 2 to 20, from 4 to 8, from 4 to 10, from 4 to 16, and from 4 to 20); “locked” nucleic acids (LNA) in which the 2′-hydroxyl is connected by a C₁₋₆ alkylene or C₁₋₆ heteroalkylene bridge to the 4′-carbon of the same ribose sugar, where exemplary bridges included methylene, propylene, ether, or amino bridges; aminoalkyl, as defined herein; aminoalkoxy, as defined herein; amino as defined herein; and amino acid, as defined herein

Generally, RNA includes the sugar group ribose, which is a 5-membered ring having an oxygen. Exemplary, non-limiting modified nucleotides include replacement of the oxygen in ribose (e.g., with S, Se, or alkylene, such as methylene or ethylene); addition of a double bond (e.g., to replace ribose with cyclopentenyl or cyclohexenyl); ring contraction of ribose (e.g., to form a 4-membered ring of cyclobutane or oxetane); ring expansion of ribose (e.g., to form a 6- or 7-membered ring having an additional carbon or heteroatom, such as for anhydrohexitol, altritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone); multicyclic forms (e.g., tricyclo; and “unlocked” forms, such as glycol nucleic acid (GNA) (e.g., R-GNA or S-GNA, where ribose is replaced by glycol units attached to phosphodiester bonds), threose nucleic acid (TNA, where ribose is replace with α-L-threofuranosyl-(3′→2′)), and peptide nucleic acid (PNA, where 2-amino-ethyl-glycine linkages replace the ribose and phosphodiester backbone). The sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose. Thus, a polynucleotide molecule can include nucleotides containing, e.g., arabinose, as the sugar. Such sugar modifications are taught International Application Number PCT/2012/058519 filed Oct. 3, 2012 and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 the contents of each of which are incorporated herein by reference in its entirety.

Modifications on the Nucleobase

The present disclosure provides for modified nucleosides and nucleotides. As described herein “nucleoside” is defined as a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”). As described herein, “nucleotide” is defined as a nucleoside including a phosphate group. The modified nucleotides may by synthesized by any useful method, as described herein (e.g., chemically, enzymatically, or recombinantly to include one or more modified or non-natural nucleosides). The polynucleotides may comprise a region or regions of linked nucleosides. Such regions may have variable backbone linkages. The linkages may be standard phosphoester linkages, in which case the polynucleotides would comprise regions of nucleotides.

The modified nucleotide base pairing encompasses not only the standard adenosine-thymine, adenosine-uracil, or guanosine-cytosine base pairs, but also base pairs formed between nucleotides and/or modified nucleotides comprising non-standard or modified bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures. One example of such non-standard base pairing is the base pairing between the modified nucleotide inosine and adenine, cytosine or uracil.

The modified nucleosides and nucleotides can include a modified nucleobase. Examples of nucleobases found in RNA include, but are not limited to, adenine, guanine, cytosine, and uracil. Examples of nucleobase found in DNA include, but are not limited to, adenine, guanine, cytosine, and thymine. Such modified nucleobases (including the distinctions between naturally occurring and non-naturally occurring) are taught in International Application Number PCT/2012/058519 filed Oct. 3, 2012 and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 the contents of each of which are incorporated herein by reference in its entirety.

Combinations of Modified Sugars, Nucleobases, and Internucleoside Linkages

The polynucleotides of the invention, e.g., the NAVs of the invention, can include a combination of modifications to the sugar, the nucleobase, and/or the internucleoside linkage. These combinations can include any one or more modifications described herein.

Examples of modified nucleotides and modified nucleotide combinations are provided below in Table 25. These combinations of modified nucleotides can be used to form the polynucleotides of the invention. Unless otherwise noted, the modified nucleotides may be completely substituted for the natural nucleotides of the polynucleotides of the invention. As a non-limiting example, the natural nucleotide uridine may be substituted with a modified nucleoside described herein. In another non-limiting example, the natural nucleotide uridine may be partially substituted (e.g., about 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99.9%) with at least one of the modified nucleoside disclosed herein. Any combination of base/sugar or linker may be incorporated into the polynucleotides of the invention and such modifcations are taught in International Application Number PCT/2012/058519 filed Oct. 3, 2012 and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 the contents of each of which are incorporated herein by reference in its entirety.

TABLE 25 Combinations Modified Nucleotide Modified Nucleotide Combination α-thio-cytidine α-thio-cytidine/5-iodo-uridine α-thio-cytidine/N1-methyl-pseudouridine α-thio-cytidine/α-thio-uridine α-thio-cytidine/5-methyl-uridine α-thio-cytidine/pseudo-uridine about 50% of the cytosines are α-thio-cytidine Pseudoisocytidine pseudoisocytidine/5-iodo-uridine pseudoisocytidine/N1-methyl-pseudouridine pseudoisocytidine/α-thio-uridine pseudoisocytidine/5-methyl-uridine pseudoisocytidine/pseudouridine about 25% of cytosines are pseudoisocytidine pseudoisocytidine/about 50% of uridines are N1- methyl-pseudouridine and about 50% of uridines are pseudouridine pseudoisocytidine/about 25% of uridines are N1- methyl-pseudouridine and about 25% of uridines are pseudouridine pyrrolo-cytidine pyrrolo-cytidine/5-iodo-uridine pyrrolo-cytidine/N1-methyl-pseudouridine pyrrolo-cytidine/α-thio-uridine pyrrolo-cytidine/5-methyl-uridine pyrrolo-cytidine/pseudouridine about 50% of the cytosines are pyrrolo-cytidine 5-methyl-cytidine 5-methyl-cytidine/5-iodo-uridine 5-methyl-cytidine/N1-methyl-pseudouridine 5-methyl-cytidine/α-thio-uridine 5-methyl-cytidine/5-methyl-uridine 5-methyl-cytidine/pseudouridine about 25% of cytosines are 5-methyl-cytidine about 50% of cytosines are 5-methyl-cytidine 5-methyl-cytidine/5-methoxy-uridine 5-methyl-cytidine/5-bromo-uridine 5-methyl-cytidine/2-thio-uridine 5-methyl-cytidine/about 50% of uridines are 2-thio-uridine about 50% of uridines are 5-methyl-cytidine/ about 50% of uridines are 2-thio-uridine N4-acetyl-cytidine N4-acetyl-cytidine/5-iodo-uridine N4-acetyl-cytidine/N1-methyl-pseudouridine N4-acetyl-cytidine/α-thio-uridine N4-acetyl-cytidine/5-methyl-uridine N4-acetyl-cytidine/pseudouridine about 50% of cytosines are N4-acetyl-cytidine about 25% of cytosines are N4-acetyl-cytidine N4-acetyl-cytidine/5-methoxy-uridine N4-acetyl-cytidine/5-bromo-uridine N4-acetyl-cytidine/2-thio-uridine about 50% of cytosines are N4-acetyl-cytidine/ about 50% of uridines are 2-thio-uridine

V. Pharmaceutical Vaccine Compositions

Formulation, Administration, Delivery and Dosing

The present invention provides pharmaceutical compositions including NAVs and NAV compositions and/or complexes optionally in combination with one or more pharmaceutically acceptable excipients.

The present inventors have discovered that NAVs are superior to current vaccines in several ways. First, subcutaneous and/or intradermal injection is better than intramuscular administration as a route of delivery. Second, the lipid nanoparticle delivery is superior to other formulations includind the protamine approach in the literature by a factor of between 10-100 fold and no additional adjuvants were found to be necessary. Third modified and formulated NAVs were superior to unmodified formulated NAVs by a factor of 50 fold.

The present invention provides NAVs and NAV pharmaceutical compositions and complexes optionally in combination with one or more pharmaceutically acceptable excipients. Pharmaceutical compositions may optionally comprise one or more additional active substances, e.g. therapeutically and/or prophylactically active substances. Pharmaceutical compositions of the present invention may be sterile and/or pyrogen-free. General considerations in the formulation and/or manufacture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21^(st) ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety).

In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase “active ingredient” generally refers to the NAVs or the polynucleotides contained therein, e.g., antigen-encoding polynucleotides, for example, RNA polynucleotides, to be delivered as described herein.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys.

Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit.

Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.

Formulations

The NAVs of the invention can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation); (4) alter the biodistribution (e.g., target to specific tissues or cell types); (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein (antigen) in vivo. In addition to traditional excipients such as any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, excipients of the present invention can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with NAVs (e.g., for transplantation into a subject), hyaluronidase, nanoparticle mimics and combinations thereof.

Accordingly, the formulations of the invention can include one or more excipients, each in an amount that may increases the stability of the NAV, increases cell transfection by the NAV, increases the expression of polynucleotides encoded protein, and/or alters the release profile of polynucleotide encoded proteins. Further, the polynucleotides of the present invention may be formulated using self-assembled nucleic acid nanoparticles.

Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of associating the active ingredient with an excipient and/or one or more other accessory ingredients.

A pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 99% (w/w) of the active ingredient. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.

In some embodiments, the formulations described herein may contain at least one polynucleotide, e.g., antigen-encoding polynucleotide. As a non-limiting example, the formulations may contain 1, 2, 3, 4 or 5 polynucleotides.

In one embodiment, the formulations described herein may comprise more than one type of polynucleotide, e.g., antigen-encoding polynucleotide. In one embodiment, the formulation may comprise a chimeric polynucleotide in linear and circular form. In another embodiment, the formulation may comprise a circular polynucleotide and an IVT polynucleotide. In yet another embodiment, the formulation may comprise an IVT polynucleotide, a chimeric polynucleotide and a circular polynucleotide.

In one embodiment the formulation may contain polynucleotide encoding proteins selected from categories such as, but not limited to, human proteins, veterinary proteins, bacterial proteins, biological proteins, antibodies, immunogenic proteins, therapeutic peptides and proteins, secreted proteins, plasma membrane proteins, cytoplasmic and cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease and/or proteins associated with non-human diseases. In one embodiment, the formulation contains at least three polynucleotides encoding proteins. In one embodiment, the formulation contains at least five polynucleotide encoding proteins.

Pharmaceutical formulations may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21^(st) Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, Md., 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.

In some embodiments, the particle size of the lipid nanoparticle may be increased and/or decreased. The change in particle size may be able to help counter biological reaction such as, but not limited to, inflammation or may increase the biological effect of the modified mRNA delivered to mammals.

Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, surface active agents and/or emulsifiers, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in the pharmaceutical formulations of the invention.

Lipidoids

The synthesis of lipidoids has been extensively described and formulations containing these compounds are particularly suited for delivery of polynucleotides (see Mahon et al., Bioconjug Chem. 2010 21:1448-1454; Schroeder et al., J Intern Med. 2010 267:9-21; Akinc et al., Nat Biotechnol. 2008 26:561-569; Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869; Siegwart et al., Proc Natl Acad Sci U.S.A. 2011 108:12996-3001; all of which are incorporated herein in their entireties).

While these lipidoids have been used to effectively deliver double stranded small interfering RNA molecules in rodents and non-human primates (see Akinc et al., Nat Biotechnol. 2008 26:561-569; Frank-Kamenetsky et al., Proc Natl Acad Sci U.S.A. 2008 105:11915-11920; Akinc et al., Mol Ther. 2009 17:872-879; Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869; Leuschner et al., Nat Biotechnol. 2011 29:1005-1010; all of which is incorporated herein in their entirety), the present disclosure describes their formulation and use in delivering NAVs or polynucleotides contained therein.

Complexes, micelles, liposomes or particles can be prepared containing these lipidoids and therefore, can result in an effective delivery of the polynucleotide, as judged by the production of an encoded protein, following the injection of a lipidoid formulation via localized and/or systemic routes of administration. Lipidoid complexes of polynucleotides can be administered by various means including, but not limited to, intravenous, intramuscular, or subcutaneous routes.

In vivo delivery of nucleic acids may be affected by many parameters, including, but not limited to, the formulation composition, nature of particle PEGylation, degree of loading, polynucleotide to lipid ratio, and biophysical parameters such as, but not limited to, particle size (Akinc et al., Mol Ther. 2009 17:872-879; herein incorporated by reference in its entirety). As an example, small changes in the anchor chain length of poly(ethylene glycol) (PEG) lipids may result in significant effects on in vivo efficacy. Formulations with the different lipidoids, including, but not limited to penta[3-(1-laurylaminopropionyl)]-triethylenetetramine hydrochloride (TETA-SLAP; aka 98N12-5, see Murugaiah et al., Analytical Biochemistry, 401:61 (2010); herein incorporated by reference in its entirety), C12-200 (including derivatives and variants), and MD1, can be tested for in vivo activity.

The lipidoid referred to herein as “98N12-5” is disclosed by Akinc et al., Mol Ther. 2009 17:872-879 and is incorporated by reference in its entirety.

The lipidoid referred to herein as “C12-200” is disclosed by Love et al., Proc Natl Acad Sci U.S.A. 2010 107:1864-1869 and Liu and Huang, Molecular Therapy. 2010 669-670; both of which are herein incorporated by reference in their entirety. The lipidoid formulations can include particles comprising either 3 or 4 or more components in addition to polynucleotides. As an example, formulations with certain lipidoids, include, but are not limited to, 98N12-5 and may contain 42% lipidoid, 48% cholesterol and 10% PEG (C14 alkyl chain length). As another example, formulations with certain lipidoids, include, but are not limited to, C12-200 and may contain 50% lipidoid, 10% disteroylphosphatidyl choline, 38.5% cholesterol, and 1.5% PEG-DMG.

In one embodiment, a polynucleotide formulated with a lipidoid for systemic intravenous administration can target the liver. For example, a final optimized intravenous formulation using polynucleotides, and comprising a lipid molar composition of 42% 98N12-5, 48% cholesterol, and 10% PEG-lipid with a final weight ratio of about 7.5 to 1 total lipid to polynucleotides, and a C14 alkyl chain length on the PEG lipid, with a mean particle size of roughly 50-60 nm, can result in the distribution of the formulation to be greater than 90% to the liver. (see, Akinc et al., Mol Ther. 2009 17:872-879; herein incorporated by reference in its entirety). In another example, an intravenous formulation using a C12-200 (see US provisional application 61/175,770 and published international application WO2010129709, each of which is herein incorporated by reference in their entirety) lipidoid may have a molar ratio of 50/10/38.5/1.5 of C12-200/disteroylphosphatidyl choline/cholesterol/PEG-DMG, with a weight ratio of 7 to 1 total lipid to polynucleotides, and a mean particle size of 80 nm may be effective to deliver polynucleotides to hepatocytes (see, Love et al., Proc Natl Acad Sci U.S.A. 2010 107:1864-1869 herein incorporated by reference in its entirety). In another embodiment, an MD1 lipidoid-containing formulation may be used to effectively deliver polynucleotides to hepatocytes in vivo.

The characteristics of optimized lipidoid formulations for intramuscular or subcutaneous routes may vary significantly depending on the target cell type and the ability of formulations to diffuse through the extracellular matrix into the blood stream. While a particle size of less than 150 nm may be desired for effective hepatocyte delivery due to the size of the endothelial fenestrae (see, Akinc et al., Mol Ther. 2009 17:872-879 herein incorporated by reference in its entirety), use of a lipidoid-formulated NAVs to deliver the formulation to other cells types including, but not limited to, endothelial cells, myeloid cells, and muscle cells may not be similarly size-limited.

Use of lipidoid formulations to deliver siRNA in vivo to other non-hepatocyte cells such as myeloid cells and endothelium has been reported (see Akinc et al., Nat Biotechnol. 2008 26:561-569; Leuschner et al., Nat Biotechnol. 2011 29:1005-1010; Cho et al. Adv. Funct. Mater. 2009 19:3112-3118; 8^(th) International Judah Folkman Conference, Cambridge, Mass. Oct. 8-9, 2010; each of which is herein incorporated by reference in its entirety). Effective delivery to myeloid cells, such as monocytes, lipidoid formulations may have a similar component molar ratio. Different ratios of lipidoids and other components including, but not limited to, disteroylphosphatidyl choline, cholesterol and PEG-DMG, may be used to optimize the formulation of the RNAVs for delivery to different cell types including, but not limited to, hepatocytes, myeloid cells, muscle cells, etc. For example, the component molar ratio may include, but is not limited to, 50% C12-200, 10% disteroylphosphatidyl choline, 38.5% cholesterol, and %1.5 PEG-DMG (see Leuschner et al., Nat Biotechnol 2011 29:1005-1010; herein incorporated by reference in its entirety). The use of lipidoid formulations for the localized delivery of nucleic acids to cells (such as, but not limited to, adipose cells and muscle cells) via either subcutaneous or intramuscular delivery, may not require all of the formulation components desired for systemic delivery, and as such may comprise only the lipidoid and the NAV.

Combinations of different lipidoids may be used to improve the efficacy of polynucleotides directed protein production as the lipidoids may be able to increase cell transfection by the RNAV; and/or increase the translation of encoded protein (see Whitehead et al., Mol. Ther. 2011, 19:1688-1694, herein incorporated by reference in its entirety).

Liposomes, Lipoplexes, and Lipid Nanoparticles

The NAVs of the invention can be formulated using one or more liposomes, lipoplexes, or lipid nanoparticles. In one embodiment, pharmaceutical compositions of NAVs include liposomes. Liposomes are artificially-prepared vesicles which may primarily be composed of a lipid bilayer and may be used as a delivery vehicle for the administration of nutrients and pharmaceutical formulations. Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV) which may be hundreds of nanometers in diameter and may contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which may be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which may be between 50 and 500 nm in diameter. Liposome design may include, but is not limited to, opsonins or ligands in order to improve the attachment of liposomes to unhealthy tissue or to activate events such as, but not limited to, endocytosis. Liposomes may contain a low or a high pH in order to improve the delivery of the pharmaceutical formulations.

The formation of liposomes may depend on the physicochemical characteristics such as, but not limited to, the pharmaceutical formulation entrapped and the liposomal ingredients, the nature of the medium in which the lipid vesicles are dispersed, the effective concentration of the entrapped substance and its potential toxicity, any additional processes involved during the application and/or delivery of the vesicles, the optimization size, polydispersity and the shelf-life of the vesicles for the intended application, and the batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products.

As a non-limiting example, liposomes such as synthetic membrane vesicles may be prepared by the methods, apparatus and devices described in US Patent Publication No. US20130177638, US20130177637, US20130177636, US20130177635, US20130177634, US20130177633, US20130183375, US20130183373 and US20130183372, the contents of each of which are herein incorporated by reference in its entirety.

In one embodiment, pharmaceutical compositions described herein may include, without limitation, liposomes such as those formed from 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA) liposomes, DiLa2 liposomes from Marina Biotech (Bothell, Wash.), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), and MC3 (US20100324120; herein incorporated by reference in its entirety) and liposomes which may deliver small molecule drugs such as, but not limited to, DOXIL® from Janssen Biotech, Inc. (Horsham, Pa.).

In one embodiment, pharmaceutical compositions described herein may include, without limitation, liposomes such as those formed from the synthesis of stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo (see Wheeler et al. Gene Therapy. 1999 6:271-281; Zhang et al. Gene Therapy. 1999 6:1438-1447; Jeffs et al. Pharm Res. 2005 22:362-372; Morrissey et al., Nat Biotechnol. 2005 2:1002-1007; Zimmermann et al., Nature. 2006 441:111-114; Heyes et al. J Contr Rel. 2005 107:276-287; Semple et al. Nature Biotech. 2010 28:172-176; Judge et al. J Clin Invest. 2009 119:661-673; deFougerolles Hum Gene Ther. 2008 19:125-132; U.S. Patent Publication No. US20130122104; all of which are incorporated herein in their entireties). The original manufacture method by Wheeler et al. was a detergent dialysis method, which was later improved by Jeffs et al. and is referred to as the spontaneous vesicle formation method. The liposome formulations are composed of 3 to 4 lipid components in addition to the polynucleotide. As an example a liposome can contain, but is not limited to, 55% cholesterol, 20% disteroylphosphatidyl choline (DSPC), 10% PEG-S-DSG, and 15% 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), as described by Jeffs et al. As another example, certain liposome formulations may contain, but are not limited to, 48% cholesterol, 20% DSPC, 2% PEG-c-DMA, and 30% cationic lipid, where the cationic lipid can be 1,2-distearloxy-N,N-dimethylaminopropane (DSDMA), DODMA, DLin-DMA, or 1,2-dilinolenyloxy-3-dimethylaminopropane (DLenDMA), as described by Heyes et al.

In some embodiments, liposome formulations may comprise from about about 25.0% cholesterol to about 40.0% cholesterol, from about 30.0% cholesterol to about 45.0% cholesterol, from about 35.0% cholesterol to about 50.0% cholesterol and/or from about 48.5% cholesterol to about 60% cholesterol. In a preferred embodiment, formulations may comprise a percentage of cholesterol selected from the group consisting of 28.5%, 31.5%, 33.5%, 36.5%, 37.0%, 38.5%, 39.0% and 43.5%. In some embodiments, formulations may comprise from about 5.0% to about 10.0% DSPC and/or from about 7.0% to about 15.0% DSPC.

In one embodiment, pharmaceutical compositions may include liposomes which may be formed to deliver polynucleotides which may encode at least one immunogen (antigen) or any other polypeptide of interest. The NAV may be encapsulated by the liposome and/or it may be contained in an aqueous core which may then be encapsulated by the liposome (see International Pub. Nos. WO2012031046, WO2012031043, WO2012030901 and WO2012006378 and US Patent Publication No. US20130189351, US20130195969 and US20130202684; the contents of each of which are herein incorporated by reference in their entirety).

In another embodiment, liposomes may be formulated for targeted delivery. As a non-limiting example, the liposome may be formulated for targeted delivery to the liver. The liposome used for targeted delivery may include, but is not limited to, the liposomes described in and methods of making liposomes described in US Patent Publication No. US20130195967, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the polynucleotide which may encode an immunogen (antigen) may be formulated in a cationic oil-in-water emulsion where the emulsion particle comprises an oil core and a cationic lipid which can interact with the polynucleotide anchoring the molecule to the emulsion particle (see International Pub. No. WO2012006380; herein incorporated by reference in its entirety).

In one embodiment, the NAVs may be formulated in a water-in-oil emulsion comprising a continuous hydrophobic phase in which the hydrophilic phase is dispersed. As a non-limiting example, the emulsion may be made by the methods described in International Publication No. WO201087791, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the lipid formulation may include at least cationic lipid, a lipid which may enhance transfection and a least one lipid which contains a hydrophilic head group linked to a lipid moiety (International Pub. No. WO2011076807 and U.S. Pub. No. 20110200582; the contents of each of which is herein incorporated by reference in their entirety). In another embodiment, the polynucleotides encoding an immunogen may be formulated in a lipid vesicle which may have crosslinks between functionalized lipid bilayers (see U.S. Pub. No. 20120177724, the contents of which is herein incorporated by reference in its entirety).

In one embodiment, the polylnucleotides may be formulated in a lipsome as described in International Patent Publication No. WO2013086526, the contents of which is herein incorporated by reference in its entirety. The NAVs may be encapsulated in a liposome using reverse pH gradients and/or optimized internal buffer compositions as described in International Patent Publication No. WO2013086526, the contents of which is herein incorporated by reference in its entirety.

In one embodiment, the NAV pharmaceutical compositions may be formulated in liposomes such as, but not limited to, DiLa2 liposomes (Marina Biotech, Bothell, Wash.), SMARTICLES® (Marina Biotech, Bothell, Wash.), neutral DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) based liposomes (e.g., siRNA delivery for ovarian cancer (Landen et al. Cancer Biology & Therapy 2006 5(12)1708-1713); herein incorporated by reference in its entirety) and hyaluronan-coated liposomes (Quiet Therapeutics, Israel).

In one embodiment, the cationic lipid may be a low molecular weight cationic lipid such as those described in US Patent Application No. 20130090372, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs may be formulated in a lipid vesicle which may have crosslinks between functionalized lipid bilayers.

In one embodiment, the NAVs may be formulated in a liposome comprising a cationic lipid. The liposome may have a molar ratio of nitrogen atoms in the cationic lipid to the phophates in the RNA (N:P ratio) of between 1:1 and 20:1 as described in International Publication No. WO2013006825, herein incorporated by reference in its entirety. In another embodiment, the liposome may have a N:P ratio of greater than 20:1 or less than 1:1.

In one embodiment, the NAVs may be formulated in a lipid-polycation complex. The formation of the lipid-polycation complex may be accomplished by methods known in the art and/or as described in U.S. Pub. No. 20120178702, herein incorporated by reference in its entirety. As a non-limiting example, the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyornithine and/or polyarginine and the cationic peptides described in International Pub. No. WO2012013326 or US Patent Pub. No. US20130142818; each of which is herein incorporated by reference in its entirety. In another embodiment, the NAVs may be formulated in a lipid-polycation complex which may further include a non-cationic lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE).

In one embodiment, the NAVs may be formulated in an aminoalcohol lipidoid. Aminoalcohol lipidoids which may be used in the present invention may be prepared by the methods described in U.S. Pat. No. 8,450,298, herein incorporated by reference in its entirety.

The liposome formulation may be influenced by, but not limited to, the selection of the cationic lipid component, the degree of cationic lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size. In one example by Semple et al. (Semple et al. Nature Biotech. 2010 28:172-176; herein incorporated by reference in its entirety), the liposome formulation was composed of 57.1% cationic lipid, 7.1% dipalmitoylphosphatidylcholine, 34.3% cholesterol, and 1.4% PEG-c-DMA. As another example, changing the composition of the cationic lipid could more effectively deliver siRNA to various antigen presenting cells (Basha et al. Mol Ther. 2011 19:2186-2200; herein incorporated by reference in its entirety). In some embodiments, liposome formulations may comprise from about 35 to about 45% cationic lipid, from about 40% to about 50% cationic lipid, from about 50% to about 60% cationic lipid and/or from about 55% to about 65% cationic lipid. In some embodiments, the ratio of lipid to mRNA in liposomes may be from about about 5:1 to about 20:1, from about 10:1 to about 25:1, from about 15:1 to about 30:1 and/or at least 30:1.

In some embodiments, the ratio of PEG in the lipid nanoparticle (LNP) formulations may be increased or decreased and/or the carbon chain length of the PEG lipid may be modified from C14 to C18 to alter the pharmacokinetics and/or biodistribution of the LNP formulations. As a non-limiting example, LNP formulations may contain from about 0.5% to about 3.0%, from about 1.0% to about 3.5%, from about 1.5% to about 4.0%, from about 2.0% to about 4.5%, from about 2.5% to about 5.0% and/or from about 3.0% to about 6.0% of the lipid molar ratio of PEG-c-DOMG (R-3-[(ω-methoxy-poly(ethyleneglycol)2000)carbamoyl)]-1,2-dimyristyloxypropyl-3-amine) (also referred to herein as PEG-DOMG) as compared to the cationic lipid, DSPC and cholesterol. In another embodiment the PEG-c-DOMG may be replaced with a PEG lipid such as, but not limited to, PEG-DSG (1,2-Distearoyl-sn-glycerol, methoxypolyethylene glycol), PEG-DMG (1,2-Dimyristoyl-sn-glycerol) and/or PEG-DPG (1,2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol). The cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, C12-200 and DLin-KC2-DMA.

In one embodiment, the NAVs may be formulated in a lipid nanoparticle such as those described in International Publication No. WO2012170930, the contents of which is herein incorporated by reference in its entirety.

In one embodiment, the NAV formulation comprising the polynucleotide is a nanoparticle which may comprise at least one lipid. The lipid may be selected from, but is not limited to, DLin-DMA, DLin-K-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG, PEGylated lipids and amino alcohol lipids. In another aspect, the lipid may be a cationic lipid such as, but not limited to, DLin-DMA, DLin-D-DMA, DLin-MC3-DMA, DLin-KC2-DMA, DODMA and amino alcohol lipids. The amino alcohol cationic lipid may be the lipids described in and/or made by the methods described in US Patent Publication No. US20130150625, herein incorporated by reference in its entirety. As a non-limiting example, the cationic lipid may be 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,2Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 1 in US20130150625); 2-amino-3-[(9Z)-octadec-9-en-1-yloxy]-2-{[(9Z)-octadec-9-en-1-yloxy]methyl}propan-1-ol (Compound 2 in US20130150625); 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-[(octyloxy)methyl]propan-1-ol (Compound 3 in US20130150625); and 2-(dimethylamino)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 4 in US20130150625); or any pharmaceutically acceptable salt or stereoisomer thereof.

Lipid nanoparticle formulations typically comprise a lipid, in particular, an ionizable cationic lipid, for example, 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), or di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), and further comprise a neutral lipid, a sterol and a molecule capable of reducing particle aggregation, for example a PEG or PEG-modified lipid.

In one embodiment, the lipid nanoparticle formulation consists essentially of (i) at least one lipid selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319); (ii) a neutral lipid selected from DSPC, DPPC, POPC, DOPE and SM; (iii) a sterol, e.g., cholesterol; and (iv) a PEG-lipid, e.g., PEG-DMG or PEG-cDMA, in a molar ratio of about 20-60% cationic lipid: 5-25% neutral lipid: 25-55% sterol; 0.5-15% PEG-lipid.

In one embodiment, the formulation includes from about 25% to about 75% on a molar basis of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), e.g., from about 35 to about 65%, from about 45 to about 65%, about 60%, about 57.5%, about 50% or about 40% on a molar basis.

In one embodiment, the formulation includes from about 0.5% to about 15% on a molar basis of the neutral lipid e.g., from about 3 to about 12%, from about 5 to about 10% or about 15%, about 10%, or about 7.5% on a molar basis. Exemplary neutral lipids include, but are not limited to, DSPC, POPC, DPPC, DOPE and SM. In one embodiment, the formulation includes from about 5% to about 50% on a molar basis of the sterol (e.g., about 15 to about 45%, about 20 to about 40%, about 40%, about 38.5%, about 35%, or about 31% on a molar basis. An exemplary sterol is cholesterol. In one embodiment, the formulation includes from about 0.5% to about 20% on a molar basis of the PEG or PEG-modified lipid (e.g., about 0.5 to about 10%, about 0.5 to about 5%, about 1.5%, about 0.5%, about 1.5%, about 3.5%, or about 5% on a molar basis. In one embodiment, the PEG or PEG modified lipid comprises a PEG molecule of an average molecular weight of 2,000 Da. In other embodiments, the PEG or PEG modified lipid comprises a PEG molecule of an average molecular weight of less than 2,000, for example around 1,500 Da, around 1,000 Da, or around 500 Da. Exemplary PEG-modified lipids include, but are not limited to, PEG-distearoyl glycerol (PEG-DMG) (also referred herein as PEG-C14 or C14-PEG), PEG-cDMA (further discussed in Reyes et al. J. Controlled Release, 107, 276-287 (2005) the contents of which are herein incorporated by reference in its entirety)

In one embodiment, the formulations of the inventions include 25-75% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), 0.5-15% of the neutral lipid, 5-50% of the sterol, and 0.5-20% of the PEG or PEG-modified lipid on a molar basis.

In one embodiment, the formulations of the inventions include 35-65% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), 3-12% of the neutral lipid, 15-45% of the sterol, and 0.5-10% of the PEG or PEG-modified lipid on a molar basis.

In one embodiment, the formulations of the inventions include 45-65% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), 5-10% of the neutral lipid, 25-40% of the sterol, and 0.5-10% of the PEG or PEG-modified lipid on a molar basis.

In one embodiment, the formulations of the inventions include about 60% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 7.5% of the neutral lipid, about 31% of the sterol, and about 1.5% of the PEG or PEG-modified lipid on a molar basis.

In one embodiment, the formulations of the inventions include about 50% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane

(DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 10% of the neutral lipid, about 38.5% of the sterol, and about 1.5% of the PEG or PEG-modified lipid on a molar basis.

In one embodiment, the formulations of the inventions include about 50% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 10% of the neutral lipid, about 35% of the sterol, about 4.5% or about 5% of the PEG or PEG-modified lipid, and about 0.5% of the targeting lipid on a molar basis.

In one embodiment, the formulations of the inventions include about 40% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 15% of the neutral lipid, about 40% of the sterol, and about 5% of the PEG or PEG-modified lipid on a molar basis.

In one embodiment, the formulations of the inventions include about 57.2% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 7.1% of the neutral lipid, about 34.3% of the sterol, and about 1.4% of the PEG or PEG-modified lipid on a molar basis.

In one embodiment, the formulations of the inventions include about 57.5% of a cationic lipid selected from the PEG lipid is PEG-cDMA (PEG-cDMA is further discussed in Reyes et al. (J. Controlled Release, 107, 276-287 (2005), the contents of which are herein incorporated by reference in its entirety), about 7.5% of the neutral lipid, about 31.5% of the sterol, and about 3.5% of the PEG or PEG-modified lipid on a molar basis.

In preferred embodiments, lipid nanoparticle formulation consists essentially of a lipid mixture in molar ratios of about 20-70% cationic lipid: 5-45% neutral lipid: 20-55% cholesterol: 0.5-15% PEG-modified lipid; more preferably in a molar ratio of about 20-60% cationic lipid: 5-25% neutral lipid: 25-55% cholesterol: 0.5-15% PEG-modified lipid.

In particular embodiments, the molar lipid ratio is approximately 50/10/38.5/1.5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG, PEG-DSG or PEG-DPG), 57.2/7.1134.3/1.4 (mol % cationic lipid/neutral lipid, e.g., DPPC/Chol/PEG-modified lipid, e.g., PEG-cDMA), 40/15/40/5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG), 50/10/35/4.5/0.5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DSG), 50/10/35/5 (cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG), 40/10/40/10 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA), 35/15/40/10 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA) or 52/13/30/5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA).

Exemplary lipid nanoparticle compositions and methods of making same are described, for example, in Semple et al. (2010) Nat. Biotechnol. 28:172-176; Jayarama et al. (2012), Angew. Chem. Int. Ed., 51: 8529-8533; and Maier et al. (2013) Molecular Therapy 21, 1570-1578 (the contents of each of which are incorporated herein by reference in their entirety).

In one embodiment, the lipid nanoparticle formulations described herein may comprise a cationic lipid, a PEG lipid and a structural lipid and optionally comprise a non-cationic lipid. As a non-limiting example, the lipid nanoparticle may comprise about 40-60% of cationic lipid, about 5-15% of a non-cationic lipid, about 1-2% of a PEG lipid and about 30-50% of a structural lipid. As another non-limiting example, the lipid nanoparticle may comprise about 50% cationic lipid, about 10% non-cationic lipid, about 1.5% PEG lipid and about 38.5% structural lipid. As yet another non-limiting example, the lipid nanoparticle may comprise about 55% cationic lipid, about 10% non-cationic lipid, about 2.5% PEG lipid and about 32.5% structural lipid. In one embodiment, the cationic lipid may be any cationic lipid described herein such as, but not limited to, DLin-KC2-DMA, DLin-MC3-DMA and L319.

In one embodiment, the lipid nanoparticle formulations described herein may be 4 component lipid nanoparticles. The lipid nanoparticle may comprise a cationic lipid, a non-cationic lipid, a PEG lipid and a structural lipid. As a non-limiting example, the lipid nanoparticle may comprise about 40-60% of cationic lipid, about 5-15% of a non-cationic lipid, about 1-2% of a PEG lipid and about 30-50% of a structural lipid. As another non-limiting example, the lipid nanoparticle may comprise about 50% cationic lipid, about 10% non-cationic lipid, about 1.5% PEG lipid and about 38.5% structural lipid. As yet another non-limiting example, the lipid nanoparticle may comprise about 55% cationic lipid, about 10% non-cationic lipid, about 2.5% PEG lipid and about 32.5% structural lipid. In one embodiment, the cationic lipid may be any cationic lipid described herein such as, but not limited to, DLin-KC2-DMA, DLin-MC3-DMA and L319.

In one embodiment, the lipid nanoparticle formulations described herein may comprise a cationic lipid, a non-cationic lipid, a PEG lipid and a structural lipid. As a non-limiting example, the lipid nanoparticle comprise about 50% of the cationic lipid DLin-KC2-DMA, about 10% of the non-cationic lipid DSPC, about 1.5% of the PEG lipid PEG-DOMG and about 38.5% of the structural lipid cholesterol. As a non-limiting example, the lipid nanoparticle comprise about 50% of the cationic lipid DLin-MC3-DMA, about 10% of the non-cationic lipid DSPC, about 1.5% of the PEG lipid PEG-DOMG and about 38.5% of the structural lipid cholesterol. As a non-limiting example, the lipid nanoparticle comprise about 50% of the cationic lipid DLin-MC3-DMA, about 10% of the non-cationic lipid DSPC, about 1.5% of the PEG lipid PEG-DMG and about 38.5% of the structural lipid cholesterol. As yet another non-limiting example, the lipid nanoparticle comprise about 55% of the cationic lipid L319, about 10% of the non-cationic lipid DSPC, about 2.5% of the PEG lipid PEG-DMG and about 32.5% of the structural lipid cholesterol.

In one embodiment, the cationic lipid may be selected from, but not limited to, a cationic lipid described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, WO201021865, WO2008103276, WO2013086373 and WO2013086354, U.S. Pat. Nos. 7,893,302, 7,404,969, 8,283,333, and U.S. Pat. No. 8,466,122 and US Patent Publication No. US20100036115, US20120202871, US20130064894, US20130129785, US20130150625, US20130178541 and US20130225836; the contents of each of which are herein incorporated by reference in their entirety. In another embodiment, the cationic lipid may be selected from, but not limited to, formula A described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638 and WO2013116126 or US Patent Publication No. US20130178541 and US20130225836; the contents of each of which is herein incorporated by reference in their entirety. In yet another embodiment, the cationic lipid may be selected from, but not limited to, formula CLI-CLXXIX of International Publication No. WO2008103276, formula CLI-CLXXIX of U.S. Pat. No. 7,893,302, formula CLI-CLXXXXII of U.S. Pat. No. 7,404,969 and formula I-VI of US Patent Publication No. US20100036115, formula I of US Patent Publication No US20130123338; each of which is herein incorporated by reference in their entirety. As a non-limiting example, the cationic lipid may be selected from (20Z,23Z)-N,N-dimethylnonacosa-20,23-dien-10-amine, (17Z,20Z)-N,N-dimemylhexacosa-17,20-dien-9-amine, (1Z,19Z)-N5N-dimethylpentacosa-1 6, 19-dien-8-amine, (13Z,16Z)-N,N-dimethyldocosa-13,16-dien-5-amine, (12Z,15Z)-N,N-dimethylhenicosa-12,15-dien-4-amine, (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-6-amine, (15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-7-amine, (18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-10-amine, (15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-5-amine, (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-4-amine, (19Z,22Z)-N,N-dimeihyloctaco sa-19,22-dien-9-amine, (18Z,21 Z)-N,N-dimethylheptacosa-18,21-dien-8-amine, (17Z,20Z)-N,N-dimethylhexacosa-17,20-dien-7-amine, (16Z,19Z)-N,N-dimethylpentacosa-16,19-dien-6-amine, (22Z,25Z)-N,N-dimethylhentriaconta-22,25-dien-10-amine, (21 Z,24Z)-N,N-dimethyltriaconta-21,24-dien-9-amine, (18Z)-N,N-dimetylheptacos-18-en-10-amine, (17Z)-N,N-dimethylhexacos-17-en-9-amine, (19Z,22Z)-N,N-dimethyloctacosa-19,22-dien-7-amine, N,N-dimethylheptacosan-10-amine, (20Z,23Z)-N-ethyl-N-methylnonacosa-20,23-dien-10-amine, 1-[(11Z,14Z)-1-nonylicosa-11,14-dien-1-yl]pyrrolidine, (20Z)-N,N-dimethylheptacos-20-en-1 0-amine, (15Z)-N,N-dimethyl eptacos-15-en-1 0-amine, (14Z)-N,N-dimethylnonacos-14-en-10-amine, (17Z)-N,N-dimethylnonacos-17-en-10-amine, (24Z)-N,N-dimethyltritriacont-24-en-10-amine, (20Z)-N,N-dimethylnonacos-20-en-1 0-amine, (22Z)-N,N-dimethylhentriacont-22-en-10-amine, (16Z)-N,N-dimethylpentacos-16-en-8-amine, (12Z,15Z)-N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine, (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]eptadecan-8-amine, 1-[(1S,2R)-2-hexylcyclopropyl]-N,N-dimethylnonadecan-10-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]nonadecan-10-amine, N,N-dimethyl-21-[(1S,2R)-2-octylcyclopropyl]henicosan-10-amine,N,N-dimethyl-1-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl}cyclopropyl]nonadecan-10-amine,N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]hexadecan-8-amine, N,N-dimethyl-[(1R,2S)-2-undecylcyclopropyl]tetradecan-5-amine, N,N-dimethyl-3-{7-[(1S,2R)-2-octylcyclopropyl]heptyl}dodecan-1-amine, 1-[(1R,2S)-2-hepty lcyclopropyl]-N,N-dimethyloctadecan-9-amine, 1-[(1S,2R)-2-decylcyclopropyl]-N,N-dimethylpentadecan-6-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]pentadecan-8-amine, R-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-amine, S-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-amine, 1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-[(octyloxy)methyl]ethyl}pyrrolidine, (2S)-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-[(5Z)-oct-5-en-1-yloxy]propan-2-amine, 1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-[(octyloxy)methyl]ethyl}azetidine, (2S)-1-(hexyloxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, (2S)-1-(heptyloxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, N,N-dimethyl-1-(nonyloxy)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, N,N-dimethyl-1-[(9Z)-octadec-9-en-1-yloxy]-3-(octyloxy)propan-2-amine; (2S)-N,N-dimethyl-1-[(6Z,9Z,12Z)-octadeca-6,9,12-trien-1-yloxy]-3-(octyloxy)propan-2-amine, (2S)-1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(pentyloxy)propan-2-amine, (2S)-1-(hexyloxy)-3-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethylpropan-2-amine, 1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, 1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, (2S)-1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-3-(hexyloxy)-N,N-dimethylpropan-2-amine, (2S)-1-[(13Z)-docos-13-en-1-yloxy]-3-(hexyloxy)-N,N-dimethylpropan-2-amine, 1-[(13Z)-docos-13-en-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, 1-[(9Z)-hexadec-9-en-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, (2R)-N,N-dimethyl-H(1-metoyloctyl)oxyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, (2R)-1-[(3,7-dimethyloctyl)oxy]-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, N,N-dimethyl-1-(octyloxy)-3-({8-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl}cyclopropyl]octyl}oxy)propan-2-amine, N,N-dimethyl-1-{[8-(2-oclylcyclopropyl)octyl]oxy}-3-(octyloxy)propan-2-amine and (11E,20Z,23Z)-N,N-dimethylnonacosa-11,20,2-trien-10-amine or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, the lipid may be a cleavable lipid such as those described in International Publication No. WO2012170889, herein incorporated by reference in its entirety.

In another embodiment, the lipid may be a cationic lipid such as, but not limited to, Formula (I) of U.S. Patent Application No. US20130064894, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the cationic lipid may be synthesized by methods known in the art and/or as described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, WO201021865, WO2013086373 and WO2013086354; the contents of each of which are herein incorporated by reference in their entirety.

In another embodiment, the cationic lipid may be a trialkyl cationic lipid. Non-limiting examples of trialkyl cationic lipids and methods of making and using the trialkyl cationic lipids are described in International Patent Publication No. WO2013126803, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the LNP formulations of the NAVs may contain PEG-c-DOMG at 3% lipid molar ratio. In another embodiment, the LNP formulations RNAVs may contain PEG-c-DOMG at 1.5% lipid molar ratio.

In one embodiment, the pharmaceutical compositions of the NAVs may include at least one of the PEGylated lipids described in International Publication No. WO2012099755, the contents of which is herein incorporated by reference in its entirety.

In one embodiment, the LNP formulation may contain PEG-DMG 2000 (1,2-dimyristoyl-sn-glycero-3-phophoethanolamine-N-[methoxy(polyethylene glycol)-2000). In one embodiment, the LNP formulation may contain PEG-DMG 2000, a cationic lipid known in the art and at least one other component. In another embodiment, the LNP formulation may contain PEG-DMG 2000, a cationic lipid known in the art, DSPC and cholesterol. As a non-limiting example, the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol. As another non-limiting example the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol in a molar ratio of 2:40:10:48 (see e.g., Geall et al., Nonviral delivery of self-amplifying RNA vaccines, PNAS 2012; PMID: 22908294; herein incorporated by reference in its entirety).

In one embodiment, the LNP formulation may be formulated by the methods described in International Publication Nos. WO2011127255 or WO2008103276, the contents of each of which is herein incorporated by reference in their entirety. As a non-limiting example, the NAVs described herein may be encapsulated in LNP formulations as described in WO2011127255 and/or WO2008103276; each of which is herein incorporated by reference in their entirety.

In one embodiment, the NAVs described herein may be formulated in a nanoparticle to be delivered by a parenteral route as described in U.S. Pub. No. US20120207845; the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs may be formulated in a lipid nanoparticle made by the methods described in US Patent Publication No US20130156845 or International Publication No WO2013093648 or WO2012024526, each of which is herein incorporated by reference in its entirety.

The lipid nanoparticles described herein may be made in a sterile environment by the system and/or methods described in US Patent Publication No. US20130164400, herein incorporated by reference in its entirety.

In one embodiment, the LNP formulation may be formulated in a nanoparticle such as a nucleic acid-lipid particle described in U.S. Pat. No. 8,492,359, the contents of which are herein incorporated by reference in its entirety. As a non-limiting example, the lipid particle may comprise one or more active agents or therapeutic agents; one or more cationic lipids comprising from about 50 mol % to about 85 mol % of the total lipid present in the particle; one or more non-cationic lipids comprising from about 13 mol % to about 49.5 mol % of the total lipid present in the particle; and one or more conjugated lipids that inhibit aggregation of particles comprising from about 0.5 mol % to about 2 mol % of the total lipid present in the particle. The nucleic acid in the nanoparticle may be the polynucleotides described herein and/or are known in the art.

In one embodiment, the LNP formulation may be formulated by the methods described in International Publication Nos. WO2011127255 or WO2008103276, the contents of each of which are herein incorporated by reference in their entirety. As a non-limiting example, modified RNA described herein may be encapsulated in LNP formulations as described in WO2011127255 and/or WO2008103276; the contents of each of which are herein incorporated by reference in their entirety.

In one embodiment, LNP formulations described herein may comprise a polycationic composition. As a non-limiting example, the polycationic composition may be selected from formula 1-60 of US Patent Publication No. US20050222064; the content of which is herein incorporated by reference in its entirety. In another embodiment, the LNP formulations comprising a polycationic composition may be used for the delivery of the modified RNA described herein in vivo and/or in vitro.

In one embodiment, the LNP formulations described herein may additionally comprise a permeability enhancer molecule. Non-limiting permeability enhancer molecules are described in US Patent Publication No. US20050222064; the content of which is herein incorporated by reference in its entirety.

In one embodiment, the NAV pharmaceutical compositions may be formulated in liposomes such as, but not limited to, DiLa2 liposomes (Marina Biotech, Bothell, Wash.), SMARTICLES® (Marina Biotech, Bothell, Wash.), neutral DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) based liposomes (e.g., siRNA delivery for ovarian cancer (Landen et al. Cancer Biology & Therapy 2006 5(12)1708-1713); herein incorporated by reference in its entirety) and hyaluronan-coated liposomes (Quiet Therapeutics, Israel).

In one embodiment, the NAVs may be formulated in a lyophilized gel-phase liposomal composition as described in US Publication No. US2012060293, herein incorporated by reference in its entirety.

The nanoparticle formulations may comprise a phosphate conjugate. The phosphate conjugate may increase in vivo circulation times and/or increase the targeted delivery of the nanoparticle. Phosphate conjugates for use with the present invention may be made by the methods described in International Application No. WO2013033438 or US Patent Publication No. US20130196948, the contents of each of which are herein incorporated by reference in its entirety. As a non-limiting example, the phosphate conjugates may include a compound of any one of the formulas described in International Application No. WO2013033438, herein incorporated by reference in its entirety.

The nanoparticle formulation may comprise a polymer conjugate. The polymer conjugate may be a water soluble conjugate. The polymer conjugate may have a structure as described in U.S. Patent Application No. 20130059360, the contents of which are herein incorporated by reference in its entirety. In one aspect, polymer conjugates with the polynucleotides of the present invention may be made using the methods and/or segmented polymeric reagents described in U.S. Patent Application No. 20130072709, herein incorporated by reference in its entirety. In another aspect, the polymer conjugate may have pendant side groups comprising ring moieties such as, but not limited to, the polymer conjugates described in US Patent Publication No. US20130196948, the contents of which is herein incorporated by reference in its entirety.

The nanoparticle formulations may comprise a conjugate to enhance the delivery of nanoparticles of the present invention in a subject. Further, the conjugate may inhibit phagocytic clearance of the nanoparticles in a subject. In one aspect, the conjugate may be a “self” peptide designed from the human membrane protein CD47 (e.g., the “self” particles described by Rodriguez et al (Science 2013 339, 971-975), herein incorporated by reference in its entirety). As shown by Rodriguez et al. the self peptides delayed macrophage-mediated clearance of nanoparticles which enhanced delivery of the nanoparticles. In another aspect, the conjugate may be the membrane protein CD47 (e.g., see Rodriguez et al. Science 2013 339, 971-975, herein incorporated by reference in its entirety). Rodriguez et al. showed that, similarly to “self” peptides, CD47 can increase the circulating particle ratio in a subject as compared to scrambled peptides and PEG coated nanoparticles.

In one embodiment, the NAVs of the present invention are formulated in nanoparticles which comprise a conjugate to enhance the delivery of the nanoparticles of the present invention in a subject. The conjugate may be the CD47 membrane or the conjugate may be derived from the CD47 membrane protein, such as the “self” peptide described previously. In another aspect the nanoparticle may comprise PEG and a conjugate of CD47 or a derivative thereof. In yet another aspect, the nanoparticle may comprise both the “self” peptide described above and the membrane protein CD47.

In another aspect, a “self” peptide and/or CD47 protein may be conjugated to a virus-like particle or pseudovirion, as described herein for delivery of the NAVs of the present invention.

In another embodiment, NAV pharmaceutical compositions comprising the polynucleotides of the present invention and a conjugate which may have a degradable linkage. Non-limiting examples of conjugates include an aromatic moiety comprising an ionizable hydrogen atom, a spacer moiety, and a water-soluble polymer. As a non-limiting example, pharmaceutical compositions comprising a conjugate with a degradable linkage and methods for delivering such pharmaceutical compositions are described in US Patent Publication No. US20130184443, the contents of which are herein incorporated by reference in its entirety.

The nanoparticle formulations may be a carbohydrate nanoparticle comprising a carbohydrate carrier and a NAV. As a non-limiting example, the carbohydrate carrier may include, but is not limited to, an anhydride-modified phytoglycogen or glycogen-type material, phtoglycogen octenyl succinate, phytoglycogen beta-dextrin, anhydride-modified phytoglycogen beta-dextrin. (See e.g., International Publication No. WO2012109121; the contents of which are herein incorporated by reference in its entirety).

Nanoparticle formulations of the present invention may be coated with a surfactant or polymer in order to improve the delivery of the particle. In one embodiment, the nanoparticle may be coated with a hydrophilic coating such as, but not limited to, PEG coatings and/or coatings that have a neutral surface charge. The hydrophilic coatings may help to deliver nanoparticles with larger payloads such as, but not limited to, NAVs within the central nervous system. As a non-limiting example nanoparticles comprising a hydrophilic coating and methods of making such nanoparticles are described in US Patent Publication No. US20130183244, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the lipid nanoparticles of the present invention may be hydrophilic polymer particles. Non-limiting examples of hydrophilic polymer particles and methods of making hydrophilic polymer particles are described in US Patent Publication No. US20130210991, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the lipid nanoparticles of the present invention may be hydrophobic polymer particles.

Lipid nanoparticle formulations may be improved by replacing the cationic lipid with a biodegradable cationic lipid which is known as a rapidly eliminated lipid nanoparticle (reLNP). Ionizable cationic lipids, such as, but not limited to, DLinDMA, DLin-KC2-DMA, and DLin-MC3-DMA, have been shown to accumulate in plasma and tissues over time and may be a potential source of toxicity. The rapid metabolism of the rapidly eliminated lipids can improve the tolerability and therapeutic index of the lipid nanoparticles by an order of magnitude from a 1 mg/kg dose to a 10 mg/kg dose in rat. Inclusion of an enzymatically degraded ester linkage can improve the degradation and metabolism profile of the cationic component, while still maintaining the activity of the reLNP formulation. The ester linkage can be internally located within the lipid chain or it may be terminally located at the terminal end of the lipid chain. The internal ester linkage may replace any carbon in the lipid chain.

In one embodiment, the internal ester linkage may be located on either side of the saturated carbon.

In one embodiment, an immune response may be elicited by delivering a lipid nanoparticle which may include a nanospecies, a polymer and an immunogen. (U.S. Publication No. 20120189700 and International Publication No. WO2012099805; each of which is herein incorporated by reference in their entirety). The polymer may encapsulate the nanospecies or partially encapsulate the nanospecies. The immunogen may be a recombinant protein, a modified RNA and/or a polynucleotide described herein. In one embodiment, the lipid nanoparticle may be formulated for use in a vaccine such as, but not limited to, against a pathogen.

Lipid nanoparticles may be engineered to alter the surface properties of particles so the lipid nanoparticles may penetrate the mucosal barrier. Mucus is located on mucosal tissue such as, but not limted to, oral (e.g., the buccal and esophageal membranes and tonsil tissue), ophthalmic, gastrointestinal (e.g., stomach, small intestine, large intestine, colon, rectum), nasal, respiratory (e.g., nasal, pharyngeal, tracheal and bronchial membranes), genital (e.g., vaginal, cervical and urethral membranes). Nanoparticles larger than 10-200 nm which are preferred for higher drug encapsulation efficiency and the ability to provide the sustained delivery of a wide array of drugs have been thought to be too large to rapidly diffuse through mucosal barriers. Mucus is continuously secreted, shed, discarded or digested and recycled so most of the trapped particles may be removed from the mucosla tissue within seconds or within a few hours. Large polymeric nanoparticles (200 nm-500 nm in diameter) which have been coated densely with a low molecular weight polyethylene glycol (PEG) diffused through mucus only 4 to 6-fold lower than the same particles diffusing in water (Lai et al. PNAS 2007 104(5):1482-487; Lai et al. Adv Drug Deliv Rev. 2009 61(2): 158-171; each of which is herein incorporated by reference in their entirety). The transport of nanoparticles may be determined using rates of permeation and/or fluorescent microscopy techniques including, but not limited to, fluorescence recovery after photobleaching (FRAP) and high resolution multiple particle tracking (MPT). As a non-limiting example, compositions which can penetrate a mucosal barrier may be made as described in U.S. Pat. No. 8,241,670 or International Patent Publication No. WO2013110028, the contents of each of which are herein incorporated by reference in its entirety.

The lipid nanoparticle engineered to penetrate mucus may comprise a polymeric material (i.e. a polymeric core) and/or a polymer-vitamin conjugate and/or a tri-block co-polymer. The polymeric material may include, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, poly(styrenes), polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. The polymeric material may be biodegradable and/or biocompatible. Non-limiting examples of biocompatible polymers are described in International Patent Publication No. WO2013116804, the contents of which are herein incorporated by reference in its entirety. The polymeric material may additionally be irradiated. As a non-limiting example, the polymeric material may be gamma irradiated (See e.g., International App. No. WO201282165, herein incorporated by reference in its entirety). Non-limiting examples of specific polymers include poly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(L-lactide) (PLLA), poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone-co-glycolide), poly(D,L-lactide-co-PEO-co-D,L-lactide), poly(D,L-lactide-co-PPO-co-D,L-lactide), polyalkyl cyanoacralate, polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA), polyethyleneglycol, poly-L-glutamic acid, poly(hydroxy acids), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol) (PEG), polyalkylene oxides (PEO), polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such as poly(vinyl acetate), polyvinyl halides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS), polyurethanes, derivatized celluloses such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, hydroxypropylcellulose, carboxymethylcellulose, polymers of acrylic acids, such as poly(methyl(meth)acrylate) (PMMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and copolymers and mixtures thereof, polydioxanone and its copolymers, polyhydroxyalkanoates, polypropylene fumarate, polyoxymethylene, poloxamers, poly(ortho)esters, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), PEG-PLGA-PEG and trimethylene carbonate, polyvinylpyrrolidone. The lipid nanoparticle may be coated or associated with a co-polymer such as, but not limited to, a block co-polymer (such as a branched polyether-polyamide block copolymer described in International Publication No. WO2013012476, herein incorporated by reference in its entirety), and (poly(ethylene glycol))-(poly(propylene oxide))-(poly(ethylene glycol)) triblock copolymer (see e.g., US Publication 20120121718 and US Publication 20100003337 and U.S. Pat. No. 8,263,665; each of which is herein incorporated by reference in their entirety). The co-polymer may be a polymer that is generally regarded as safe (GRAS) and the formation of the lipid nanoparticle may be in such a way that no new chemical entities are created. For example, the lipid nanoparticle may comprise poloxamers coating PLGA nanoparticles without forming new chemical entities which are still able to rapidly penetrate human mucus (Yang et al. Angew. Chem. Int. Ed. 2011 50:2597-2600; the contents of which are herein incorporated by reference in its entirety). A non-limiting scalable method to produce nanoparticles which can penetrate human mucus is described by Xu et al. (See e.g., J Control Release 2013, 170(2):279-86; the contents of which are herein incorporated by reference in its entirety).

The vitamin of the polymer-vitamin conjugate may be vitamin E. The vitamin portion of the conjugate may be substituted with other suitable components such as, but not limited to, vitamin A, vitamin E, other vitamins, cholesterol, a hydrophobic moiety, or a hydrophobic component of other surfactants (e.g., sterol chains, fatty acids, hydrocarbon chains and alkylene oxide chains).

The lipid nanoparticle engineered to penetrate mucus may include surface altering agents such as, but not limited to, polynucleotides, anionic proteins (e.g., bovine serum albumin), surfactants (e.g., cationic surfactants such as for example dimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives (e.g., cyclodextrin), nucleic acids, polymers (e.g., heparin, polyethylene glycol and poloxamer), mucolytic agents (e.g., N-acetylcysteine, mugwort, bromelain, papain, clerodendrum, acetylcysteine, bromhexine, carbocisteine, eprazinone, mesna, ambroxol, sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosin (34 dornase alfa, neltenexine, erdosteine) and various DNases including rhDNase. The surface altering agent may be embedded or enmeshed in the particle's surface or disposed (e.g., by coating, adsorption, covalent linkage, or other process) on the surface of the lipid nanoparticle. (see e.g., US Publication 20100215580 and US Publication 20080166414 and US20130164343; the contents of each of which is herein incorporated by reference in their entirety).

In one embodiment, the mucus penetrating lipid nanoparticles may comprise at least one polynucleotide described herein. The polynucleotide may be encapsulated in the lipid nanoparticle and/or disposed on the surface of the paricle. The polynucleotide may be covalently coupled to the lipid nanoparticle. Formulations of mucus penetrating lipid nanoparticles may comprise a plurality of nanoparticles. Further, the formulations may contain particles which may interact with the mucus and alter the structural and/or adhesive properties of the surrounding mucus to decrease mucoadhesion which may increase the delivery of the mucus penetrating lipid nanoparticles to the mucosal tissue.

In another embodiment, the mucus penetrating lipid nanoparticles may be a hypotonic formulation comprising a mucosal penetration enhancing coating. The formulation may be hypotonice for the epithelium to which it is being delivered. Non-limiting examples of hypotonic formulations may be found in International Patent Publication No. WO2013110028, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, in order to enhance the delivery through the mucosal barrier the NAV formulation may comprise or be a hypotonic solution. Hypotonic solutions were found to increase the rate at which mucoinert particles such as, but not limited to, mucus-penetrating particles, were able to reach the vaginal epithelial surface (See e.g., Ensign et al. Biomaterials 2013 34(28):6922-9; the contents of which is herein incorporated by reference in its entirety).

In one embodiment, the NAV is formulated as a lipoplex, such as, without limitation, the ATUPLEX™ system, the DACC system, the DBTC system and other siRNA-lipoplex technology from Silence Therapeutics (London, United Kingdom), STEMFECT™ from STEMGENT® (Cambridge, Mass.), and polyethylenimine (PEI) or protamine-based targeted and non-targeted delivery of nucleic acids acids (Aleku et al. Cancer Res. 2008 68:9788-9798; Strumberg et al. Int J Clin Pharmacol Ther 2012 50:76-78; Santel et al., Gene Ther 2006 13:1222-1234; Santel et al., Gene Ther 2006 13:1360-1370; Gutbier et al., Pulm Pharmacol. Ther. 2010 23:334-344; Kaufmann et al. Microvasc Res 2010 80:286-293Weide et al. J Immunother. 2009 32:498-507; Weide et al. J Immunother. 2008 31:180-188; Pascolo Expert Opin. Biol. Ther. 4:1285-1294; Fotin-Mleczek et al., 2011 J. Immunother. 34:1-15; Song et al., Nature Biotechnol. 2005, 23:709-717; Peer et al., Proc Natl Acad Sci USA. 2007 6; 104:4095-4100; deFougerolles Hum Gene Ther. 2008 19:125-132; all of which are incorporated herein by reference in its entirety).

In one embodiment such formulations may also be constructed or compositions altered such that they passively or actively are directed to different cell types in vivo, including but not limited to hepatocytes, immune cells, tumor cells, endothelial cells, antigen presenting cells, and leukocytes (Akinc et al. Mol Ther. 2010 18:1357-1364; Song et al., Nat Biotechnol. 2005 23:709-717; Judge et al., J Clin Invest. 2009 119:661-673; Kaufmann et al., Microvasc Res 2010 80:286-293; Santel et al., Gene Ther 2006 13:1222-1234; Santel et al., Gene Ther 2006 13:1360-1370;

Gutbier et al., Pulm Pharmacol. Ther. 2010 23:334-344; Basha et al., Mol. Ther. 2011 19:2186-2200; Fenske and Cullis, Expert Opin Drug Deliv. 2008 5:25-44; Peer et al., Science. 2008 319:627-630; Peer and Lieberman, Gene Ther. 2011 18:1127-1133; all of which are incorporated herein by reference in its entirety). One example of passive targeting of formulations to liver cells includes the DLin-DMA, DLin-KC2-DMA and DLin-MC3-DMA-based lipid nanoparticle formulations which have been shown to bind to apolipoprotein E and promote binding and uptake of these formulations into hepatocytes in vivo (Akinc et al. Mol Ther. 2010 18:1357-1364; herein incorporated by reference in its entirety). Formulations can also be selectively targeted through expression of different ligands on their surface as exemplified by, but not limited by, folate, transferrin, N-acetylgalactosamine (GalNAc), and antibody targeted approaches (Kolhatkar et al., Curr Drug Discov Technol. 2011 8:197-206; Musacchio and Torchilin, Front Biosci. 2011 16:1388-1412; Yu et al., Mol Membr Biol. 2010 27:286-298; Patil et al., Crit Rev Ther Drug Carrier Syst. 2008 25:1-61; Benoit et al., Biomacromolecules. 2011 12:2708-2714; Zhao et al., Expert Opin Drug Deliv. 2008 5:309-319; Akinc et al., Mol Ther. 2010 18:1357-1364; Srinivasan et al., Methods Mol Biol. 2012 820:105-116; Ben-Arie et al., Methods Mol Biol. 2012 757:497-507; Peer 2010 J Control Release. 20:63-68; Peer et al., Proc Natl Acad Sci USA. 2007 104:4095-4100; Kim et al., Methods Mol Biol. 2011 721:339-353; Subramanya et al., Mol Ther. 2010 18:2028-2037; Song et al., Nat Biotechnol. 2005 23:709-717; Peer et al., Science. 2008 319:627-630; Peer and Lieberman, Gene Ther. 2011 18:1127-1133; all of which are incorporated herein by reference in its entirety).

In one embodiment, the NAV is formulated as a solid lipid nanoparticle. A solid lipid nanoparticle (SLN) may be spherical with an average diameter between 10 to 1000 nm. SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and may be stabilized with surfactants and/or emulsifiers. In a further embodiment, the lipid nanoparticle may be a self-assembly lipid-polymer nanoparticle (see Zhang et al., ACS Nano, 2008, 2 (8), pp 1696-1702; the contents of which are herein incorporated by reference in its entirety). As a non-limiting example, the SLN may be the SLN described in International Patent Publication No. WO2013105101, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the SLN may be made by the methods or processes described in International Patent Publication No. WO2013105101, the contents of which are herein incorporated by reference in its entirety.

Liposomes, lipoplexes, or lipid nanoparticles may be used to improve the efficacy of polynucleotides directed protein production as these formulations may be able to increase cell transfection by the NAV; and/or increase the translation of encoded protein. One such example involves the use of lipid encapsulation to enable the effective systemic delivery of polyplex plasmid DNA (Heyes et al., Mol Ther.

2007 15:713-720; herein incorporated by reference in its entirety). The liposomes, lipoplexes, or lipid nanoparticles may also be used to increase the stability of the polynucleotide.

In one embodiment, the NAVs of the present invention can be formulated for controlled release and/or targeted delivery. As used herein, “controlled release” refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome. In one embodiment, the RNAVs may be encapsulated into a delivery agent described herein and/or known in the art for controlled release and/or targeted delivery. As used herein, the term “encapsulate” means to enclose, surround or encase. As it relates to the formulation of the compounds of the invention, encapsulation may be substantial, complete or partial. The term “substantially encapsulated” means that at least greater than 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.9 or greater than 99.999% of the pharmaceutical composition or compound of the invention may be enclosed, surrounded or encased within the delivery agent. “Partially encapsulation” means that less than 10, 10, 20, 30, 40 50 or less of the pharmaceutical composition or compound of the invention may be enclosed, surrounded or encased within the delivery agent. Advantageously, encapsulation may be determined by measuring the escape or the activity of the pharmaceutical composition or compound of the invention using fluorescence and/or electron micrograph. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the pharmaceutical composition or compound of the invention are encapsulated in the delivery agent.

In one embodiment, the controlled release formulation may include, but is not limited to, tri-block co-polymers. As a non-limiting example, the formulation may include two different types of tri-block co-polymers (International Pub. No. WO2012131104 and WO2012131106; the contents of each of which is herein incorporated by reference in its entirety).

In another embodiment, the NAVs may be encapsulated into a lipid nanoparticle or a rapidly eliminated lipid nanoparticle and the lipid nanoparticles or a rapidly eliminated lipid nanoparticle may then be encapsulated into a polymer, hydrogel and/or surgical sealant described herein and/or known in the art. As a non-limiting example, the polymer, hydrogel or surgical sealant may be PLGA, ethylene vinyl acetate (EVAc), poloxamer, GELSITE® (Nanotherapeutics, Inc. Alachua, Fla.), HYLENEX® (Halozyme Therapeutics, San Diego Calif.), surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, Ga.), TISSELL® (Baxter International, Inc Deerfield, Ill.), PEG-based sealants, and COSEAL® (Baxter International, Inc Deerfield, Ill.).

In another embodiment, the lipid nanoparticle may be encapsulated into any polymer known in the art which may form a gel when injected into a subject. As another non-limiting example, the lipid nanoparticle may be encapsulated into a polymer matrix which may be biodegradable.

In one embodiment, the the NAV formulation for controlled release and/or targeted delivery may also include at least one controlled release coating. Controlled release coatings include, but are not limited to, OPADRY®, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, EUDRAGIT RL®, EUDRAGIT RS® and cellulose derivatives such as ethylcellulose aqueous dispersions (AQUACOAT® and SURELEASE®).

In one embodiment, the NAV controlled release and/or targeted delivery formulation may comprise at least one degradable polyester which may contain polycationic side chains. Degradeable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof. In another embodiment, the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.

In one embodiment, the NAV controlled release and/or targeted delivery formulation comprising at least one polynucleotide may comprise at least one PEG and/or PEG related polymer derivatives as described in U.S. Pat. No. 8,404,222, herein incorporated by reference in its entirety.

In another embodiment, the NAV controlled release delivery formulation comprising at least one polynucleotide may be the controlled release polymer system described in US20130130348, herein incorporated by reference in its entirety.

In one embodiment, the the NAVs of the present invention may be encapsulated in a therapeutic nanoparticle, referred to herein as “therapeutic nanoparticle RNAVs.” Therapeutic nanoparticles may be formulated by methods described herein and known in the art such as, but not limited to, International Pub Nos. WO2010005740, WO2010030763, WO2010005721, WO2010005723, WO2012054923, US Pub. Nos. US20110262491, US20100104645, US20100087337, US20100068285, US20110274759, US20100068286, US20120288541, US20130123351 and US20130230567 and U.S. Pat. Nos. 8,206,747, 8,293,276, 8,318,208 and U.S. Pat. No. 8,318,211; the contents of each of which are herein incorporated by reference in their entirety. In another embodiment, therapeutic polymer nanoparticles may be identified by the methods described in US Pub No. US20120140790, the contents of which is herein incorporated by reference in its entirety.

In one embodiment, the therapeutic nanoparticle NAV may be formulated for sustained release. As used herein, “sustained release” refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. The period of time may include, but is not limited to, hours, days, weeks, months and years. As a non-limiting example, the sustained release nanoparticle may comprise a polymer and a therapeutic agent such as, but not limited to, the the polynucleotides of the present invention (see International Pub No. 2010075072 and US Pub No. US20100216804, US20110217377 and US20120201859, each of which is herein incorporated by reference in their entirety). In another non-limiting example, the sustained release formulation may comprise agents which permit persistent bioavailability such as, but not limited to, crystals, macromolecular gels and/or particulate suspensions (see US Patent Publication No US20130150295, the contents of which is herein incorporated by reference in its entirety).

In one embodiment, the therapeutic nanoparticle NAVs may be formulated to be target specific. As a non-limiting example, the thereapeutic nanoparticles may include a corticosteroid (see International Pub. No. WO2011084518; herein incorporated by reference in its entirety). As a non-limiting example, the therapeutic nanoparticles may be formulated in nanoparticles described in International Pub No. WO2008121949, WO2010005726, WO2010005725, WO2011084521 and US Pub No. US20100069426, US20120004293 and US20100104655, each of which is herein incorporated by reference in their entirety.

In one embodiment, the nanoparticles of the present invention may comprise a polymeric matrix. As a non-limiting example, the nanoparticle may comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester) or combinations thereof.

In one embodiment, the therapeutic nanoparticle comprises a diblock copolymer. In one embodiment, the diblock copolymer may include PEG in combination with a polymer such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester) or combinations thereof. In another embodiment, the diblock copolymer may comprise the diblock copolymers described in European Patent Publication No. the contents of which are herein incorporated by reference in its entirety. In yet another embodiment, the diblock copolymer may be a high-X diblock copolymer such as those described in International Patent Publication No. WO2013120052, the contents of which are herein incorporated by reference in its entirety.

As a non-limiting example the therapeutic nanoparticle comprises a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and U.S. Pat. No. 8,236,330, each of which is herein incorporated by reference in their entirety). In another non-limiting example, the therapeutic nanoparticle is a stealth nanoparticle comprising a diblock copolymer of PEG and PLA or PEG and PLGA (see U.S. Pat. No. 8,246,968 and International Publication No. WO2012166923, the contents of each of which are herein incorporated by reference in its entirety). In yet another non-limiting example, the therapeutic nanoparticle is a stealth nanoparticle or a target-specific stealth nanoparticle as described in US Patent Publication No. US20130172406, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the therapeutic nanoparticle may comprise a multiblock copolymer (See e.g., U.S. Pat. Nos. 8,263,665 and 8,287,910 and US Patent Pub. No. US20130195987; the contents of each of which are herein incorporated by reference in its entirety).

In yet another non-limiting example, the lipid nanoparticle comprises the block copolymer PEG-PLGA-PEG (see e.g., the thermosensitive hydrogel (PEG-PLGA-PEG) was used as a TGF-beta1 gene delivery vehicle in Lee et al. Thermosensitive Hydrogel as a Tgf-β1 Gene Delivery Vehicle Enhances Diabetic Wound Healing. Pharmaceutical Research, 2003 20(12): 1995-2000; as a controlled gene delivery system in Li et al. Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel. Pharmaceutical Research 2003 20(6):884-888; and Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253; each of which is herein incorporated by reference in its entirety). The NAVs of the present invention may be formulated in lipid nanoparticles comprising the PEG-PLGA-PEG block copolymer.

In one embodiment, the therapeutic nanoparticle may comprise a multiblock copolymer (See e.g., U.S. Pat. Nos. 8,263,665 and 8,287,910 and US Patent Pub. No. US20130195987; the contents of each of which are herein incorporated by reference in its entirety).

In one embodiment, the block copolymers described herein may be included in a polyion complex comprising a non-polymeric micelle and the block copolymer. (See e.g., U.S. Pub. No. 20120076836; herein incorporated by reference in its entirety).

In one embodiment, the therapeutic nanoparticle may comprise at least one acrylic polymer. Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof.

In one embodiment, the therapeutic nanoparticles may comprise at least one poly(vinyl ester) polymer. The poly(vinyl ester) polymer may be a copolymer such as a random copolymer. As a non-limiting example, the random copolymer may have a structure such as those described in International Application No. WO2013032829 or US Patent Publication No US20130121954, the contents of which are herein incorporated by reference in its entirety. In one aspect, the poly(vinyl ester) polymers may be conjugated to the polynucleotides described herein. In another aspect, the poly(vinyl ester) polymer which may be used in the present invention may be those described in, herein incorporated by reference in its entirety.

In one embodiment, the therapeutic nanoparticle may comprise at least one diblock copolymer. The diblock copolymer may be, but it not limited to, a poly(lactic) acid-poly(ethylene)glycol copolymer (see e.g., International Patent Publication No. WO2013044219; herein incorporated by reference in its entirety). As a non-limiting example, the therapeutic nanoparticle may be used to treat cancer (see International publication No. WO2013044219; herein incorporated by reference in its entirety).

In one embodiment, the therapeutic nanoparticles may comprise at least one cationic polymer described herein and/or known in the art.

In one embodiment, the therapeutic nanoparticles may comprise at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly(amidoamine) dendrimers, poly(beta-amino esters) (See e.g., U.S. Pat. No. 8,287,849; herein incorporated by reference in its entirety) and combinations thereof.

In another embodiment, the nanoparticles described herein may comprise an amine cationic lipid such as those described in International Patent Application No. WO2013059496, the contents of which are herein incorporated by reference in its entirety. In one aspect the cationic lipids may have an amino-amine or an amino-amide moiety.

In one embodiment, the therapeutic nanoparticles may comprise at least one degradable polyester which may contain polycationic side chains. Degradeable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof. In another embodiment, the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.

In another embodiment, the therapeutic nanoparticle may include a conjugation of at least one targeting ligand. The targeting ligand may be any ligand known in the art such as, but not limited to, a monoclonal antibody. (Kirpotin et al, Cancer Res. 2006 66:6732-6740; herein incorporated by reference in its entirety).

In one embodiment, the therapeutic nanoparticle may be formulated in an aqueous solution which may be used to target cancer (see International Pub No. WO2011084513 and US Pub No. US20110294717, each of which is herein incorporated by reference in their entirety).

In one embodiment, the therapeutic nanoparticle NAVs, e.g., therapeutic nanoparticles comprising at least one NAV may be formulated using the methods described by Podobinski et al in U.S. Pat. No. 8,404,799, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs may be encapsulated in, linked to and/or associated with synthetic nanocarriers. Synthetic nanocarriers include, but are not limited to, those described in International Pub. Nos. WO2010005740, WO2010030763, WO201213501, WO2012149252, WO2012149255, WO2012149259, WO2012149265, WO2012149268, WO2012149282, WO2012149301, WO2012149393, WO2012149405, WO2012149411, WO2012149454 and WO2013019669, and US Pub. Nos. US20110262491, US20100104645, US20100087337 and US20120244222, each of which is herein incorporated by reference in their entirety. The synthetic nanocarriers may be formulated using methods known in the art and/or described herein. As a non-limiting example, the synthetic nanocarriers may be formulated by the methods described in International Pub Nos. WO2010005740, WO2010030763 and WO201213501 and US Pub. Nos. US20110262491, US20100104645, US20100087337 and US2012024422, each of which is herein incorporated by reference in their entirety. In another embodiment, the synthetic nanocarrier formulations may be lyophilized by methods described in International Pub. No. WO2011072218 and U.S. Pat. No. 8,211,473; the content of each of which is herein incorporated by reference in their entirety. In yet another embodiment, formulations of the present invention, including, but not limited to, synthetic nanocarriers, may be lyophilized or reconstituted by the methods described in US Patent Publication No. US20130230568, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the synthetic nanocarriers may contain reactive groups to release the polynucleotides described herein (see International Pub. No. WO20120952552 and US Pub No. US20120171229, each of which is herein incorporated by reference in their entirety).

In one embodiment, the synthetic nanocarriers may contain an immunostimulatory agent to enhance the immune response from delivery of the synthetic nanocarrier. As a non-limiting example, the synthetic nanocarrier may comprise a Th1 immunostimulatory agent which may enhance a Th1-based response of the immune system (see International Pub No. WO2010123569 and US Pub. No. US20110223201, each of which is herein incorporated by reference in its entirety).

In one embodiment, the synthetic nanocarriers may be formulated for targeted release. In one embodiment, the synthetic nanocarrier is formulated to release the polynucleotides at a specified pH and/or after a desired time interval. As a non-limiting example, the synthetic nanoparticle may be formulated to release the NAVs after 24 hours and/or at a pH of 4.5 (see International Pub. Nos. WO2010138193 and WO2010138194 and US Pub Nos. US20110020388 and US20110027217, each of which is herein incorporated by reference in their entireties).

In one embodiment, the synthetic nanocarriers may be formulated for controlled and/or sustained release of the polynucleotides described herein. As a non-limiting example, the synthetic nanocarriers for sustained release may be formulated by methods known in the art, described herein and/or as described in International Pub No. WO2010138192 and US Pub No. 20100303850, each of which is herein incorporated by reference in their entirety.

In one embodiment, the NAV may be formulated for controlled and/or sustained release wherein the formulation comprises at least one polymer that is a crystalline side chain (CYSC) polymer. CYSC polymers are described in U.S. Pat. No. 8,399,007, herein incorporated by reference in its entirety.

In one embodiment, the synthetic nanocarrier may be formulated for use as a vaccine. In one embodiment, the synthetic nanocarrier may encapsulate at least one polynucleotide which encode at least one antigen. As a non-limiting example, the synthetic nanocarrier may include at least one antigen and an excipient for a vaccine dosage form (see International Pub No. WO2011150264 and US Pub No. US20110293723, each of which is herein incorporated by reference in their entirety). As another non-limiting example, a vaccine dosage form may include at least two synthetic nanocarriers with the same or different antigens and an excipient (see International Pub No. WO2011150249 and US Pub No. US20110293701, each of which is herein incorporated by reference in their entirety). The vaccine dosage form may be selected by methods described herein, known in the art and/or described in International Pub No. WO2011150258 and US Pub No. US20120027806, each of which is herein incorporated by reference in their entirety).

In one embodiment, the synthetic nanocarrier may comprise at least one polynucleotide which encodes at least one adjuvant. As non-limiting example, the adjuvant may comprise dimethyldioctadecylammonium-bromide, dimethyldioctadecylammonium-chloride, dimethyldioctadecylammonium-phosphate or dimethyldioctadecylammonium-acetate (DDA) and an apolar fraction or part of said apolar fraction of a total lipid extract of a mycobacterium (See e.g, U.S. Pat. No. 8,241,610; herein incorporated by reference in its entirety). In another embodiment, the synthetic nanocarrier may comprise at least one polynucleotide and an adjuvant. As a non-limiting example, the synthetic nanocarrier comprising and adjuvant may be formulated by the methods described in International Pub No. WO2011150240 and US Pub No. US20110293700, each of which is herein incorporated by reference in its entirety.

In one embodiment, the synthetic nanocarrier may encapsulate at least one polynucleotide which encodes a peptide, fragment or region from a virus. As a non-limiting example, the synthetic nanocarrier may include, but is not limited to, the nanocarriers described in International Pub No. WO2012024621, WO201202629, WO2012024632 and US Pub No. US20120064110, US20120058153 and US20120058154, each of which is herein incorporated by reference in their entirety.

In one embodiment, the synthetic nanocarrier may be coupled to a polynucleotide which may be able to trigger a humoral and/or cytotoxic T lymphocyte (CTL) response (See e.g., International Publication No. WO2013019669, herein incorporated by reference in its entirety).

In one embodiment, the NAV may be encapsulated in, linked to and/or associated with zwitterionic lipids. Non-limiting examples of zwitterionic lipids and methods of using zwitterionic lipids are described in US Patent Publication No. US20130216607, the contents of which are herein incorporated by reference in its entirety. In one aspect, the zwitterionic lipids may be used in the liposomes and lipid nanoparticles described herein.

In one embodiment, the NAV may be formulated in colloid nanocarriers as described in US Patent Publication No. US20130197100, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the nanoparticle may be optimized for oral administration. The nanoparticle may comprise at least one cationic biopolymer such as, but not limited to, chitosan or a derivative thereof. As a non-limiting example, the nanoparticle may be formulated by the methods described in U.S. Pub. No. 20120282343; herein incorporated by reference in its entirety.

In some embodiments, LNPs comprise the lipid KL52 (an amino-lipid disclosed in U.S. Application Publication No. 2012/0295832 expressly incorporated herein by reference in its entirety). Activity and/or safety (as measured by examining one or more of ALT/AST, white blood cell count and cytokine induction) of LNP administration may be improved by incorporation of such lipids. LNPs comprising KL52 may be administered intravenously and/or in one or more doses. In some embodiments, administration of LNPs comprising KL52 results in equal or improved mRNA and/or protein expression as compared to LNPs comprising MC3.

In some embodiments, NAV may be delivered using smaller LNPs. Such particles may comprise a diameter from below 0.1 um up to 100 nm such as, but not limited to, less than 0.1 um, less than 1.0 um, less than 5 um, less than 10 um, less than 15 um, less than 20 um, less than 25 um, less than 30 um, less than 35 um, less than 40 um, less than 50 um, less than 55 um, less than 60 um, less than 65 um, less than 70 um, less than 75 um, less than 80 um, less than 85 um, less than 90 um, less than 95 um, less than 100 um, less than 125 um, less than 150 um, less than 175 um, less than 200 um, less than 225 um, less than 250 um, less than 275 um, less than 300 um, less than 325 um, less than 350 um, less than 375 um, less than 400 um, less than 425 um, less than 450 um, less than 475 um, less than 500 um, less than 525 um, less than 550 um, less than 575 um, less than 600 um, less than 625 um, less than 650 um, less than 675 um, less than 700 um, less than 725 um, less than 750 um, less than 775 um, less than 800 um, less than 825 um, less than 850 um, less than 875 um, less than 900 um, less than 925 um, less than 950 um, less than 975 um,

In another embodiment, NAVs may be delivered using smaller LNPs which may comprise a diameter from about 1 nm to about 100 nm, from about 1 nm to about 10 nm, about 1 nm to about 20 nm, from about 1 nm to about 30 nm, from about 1 nm to about 40 nm, from about 1 nm to about 50 nm, from about 1 nm to about 60 nm, from about 1 nm to about 70 nm, from about 1 nm to about 80 nm, from about 1 nm to about 90 nm, from about 5 nm to about from 100 nm, from about 5 nm to about 10 nm, about 5 nm to about 20 nm, from about 5 nm to about 30 nm, from about 5 nm to about 40 nm, from about 5 nm to about 50 nm, from about 5 nm to about 60 nm, from about 5 nm to about 70 nm, from about 5 nm to about 80 nm, from about 5 nm to about 90 nm, about 10 to about 50 nM, from about 20 to about 50 nm, from about 30 to about 50 nm, from about 40 to about 50 nm, from about 20 to about 60 nm, from about 30 to about 60 nm, from about 40 to about 60 nm, from about 20 to about 70 nm, from about 30 to about 70 nm, from about 40 to about 70 nm, from about 50 to about 70 nm, from about 60 to about 70 nm, from about 20 to about 80 nm, from about 30 to about 80 nm, from about 40 to about 80 nm, from about 50 to about 80 nm, from about 60 to about 80 nm, from about 20 to about 90 nm, from about 30 to about 90 nm, from about 40 to about 90 nm, from about 50 to about 90 nm, from about 60 to about 90 nm and/or from about 70 to about 90 nm.

In some embodiments, such LNPs are synthesized using methods comprising microfluidic mixers. Exemplary microfluidic mixers may include, but are not limited to a slit interdigitial micromixer including, but not limited to those manufactured by Microinnova (Allerheiligen bei Wildon, Austria) and/or a staggered herringbone micromixer (SHM) (Zhigaltsev, I. V. et al., Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing have been published (Langmuir. 2012. 28:3633-40; Belliveau, N. M. et al., Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Molecular Therapy-Nucleic Acids. 2012. 1:e37; Chen, D. et al., Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. J Am Chem Soc. 2012. 134(16):6948-51; each of which is herein incorporated by reference in its entirety). In some embodiments, methods of LNP generation comprising SHM, further comprise the mixing of at least two input streams wherein mixing occurs by microstructure-induced chaotic advection (MICA). According to this method, fluid streams flow through channels present in a herringbone pattern causing rotational flow and folding the fluids around each other. This method may also comprise a surface for fluid mixing wherein the surface changes orientations during fluid cycling. Methods of generating LNPs using SHM include those disclosed in U.S. Application Publication Nos. 2004/0262223 and 2012/0276209, each of which is expressly incorporated herein by reference in their entirety.

In one embodiment, the NAV of the present invention may be formulated in lipid nanoparticles created using a micromixer such as, but not limited to, a Slit Interdigital Microstructured Mixer (SIMM-V2) or a Standard Slit Interdigital Micro Mixer (SSIMM) or Caterpillar (CPMM) or Impinging-jet (IJMM) from the Institut für Mikrotechnik Mainz GmbH, Mainz Germany).

In one embodiment, the NAVs of the present invention may be formulated in lipid nanoparticles created using microfluidic technology (see Whitesides, George M. The Origins and the Future of Microfluidics. Nature, 2006 442: 368-373; and Abraham et al. Chaotic Mixer for Microchannels. Science, 2002 295: 647-651; each of which is herein incorporated by reference in its entirety). As a non-limiting example, controlled microfluidic formulation includes a passive method for mixing streams of steady pressure-driven flows in micro channels at a low Reynolds number (See e.g., Abraham et al. Chaotic Mixer for Microchannels. Science, 2002 295: 647-651; which is herein incorporated by reference in its entirety).

In one embodiment, the NAVs of the present invention may be formulated in lipid nanoparticles created using a micromixer chip such as, but not limited to, those from Harvard Apparatus (Holliston, Mass.) or Dolomite Microfluidics (Royston, UK). A micromixer chip can be used for rapid mixing of two or more fluid streams with a split and recombine mechanism.

In one embodiment, the NAVs of the invention may be formulated for delivery using the drug encapsulating microspheres described in International Patent Publication No. WO2013063468 or U.S. Pat. No. 8,440,614, each of which is herein incorporated by reference in its entirety. The microspheres may comprise a compound of the formula (I), (II), (III), (IV), (V) or (VI) as described in International Patent Publication No. WO2013063468, the contents of which are herein incorporated by reference in its entirety. In another aspect, the amino acid, peptide, polypeptide, lipids (APPL) are useful in delivering the NAVs of the invention to cells (see International Patent Publication No. WO2013063468, the contents of which is herein incorporated by reference in its entirety).

In one embodiment, the NAVs of the invention may be formulated in lipid nanoparticles having a diameter from about 10 to about 100 nm such as, but not limited to, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm, about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and/or about 90 to about 100 nm.

In one embodiment, the lipid nanoparticles may have a diameter from about 10 to 500 nm.

In one embodiment, the lipid nanoparticle may have a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm.

In one aspect, the lipid nanoparticle may be a limit size lipid nanoparticle described in International Patent Publication No. WO2013059922, the contents of which are herein incorporated by reference in its entirety. The limit size lipid nanoparticle may comprise a lipid bilayer surrounding an aqueous core or a hydrophobic core; where the lipid bilayer may comprise a phospholipid such as, but not limited to, diacylphosphatidylcholine, a diacylphosphatidylethanolamine, a ceramide, a sphingomyelin, a dihydrosphingomyelin, a cephalin, a cerebroside, a C8-C20 fatty acid diacylphophatidylcholine, and 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC). In another aspect the limit size lipid nanoparticle may comprise a polyethylene glycol-lipid such as, but not limited to, DLPE-PEG, DMPE-PEG, DPPC-PEG and DSPE-PEG.

In one embodiment, the NAVs may be delivered, localized and/or concentrated in a specific location using the delivery methods described in International Patent Publication No. WO2013063530, the contents of which are herein incorporated by reference in its entirety. As a non-limiting example, a subject may be administered an empty polymeric particle prior to, simultaneously with or after delivering the NAVs to the subject. The empty polymeric particle undergoes a change in volume once in contact with the subject and becomes lodged, embedded, immobilized or entrapped at a specific location in the subject.

In one embodiment, the NAVs may be formulated in an active substance release system (See e.g., US Patent Publication No. US20130102545, the contents of which is herein incorporated by reference in its entirety). The active substance release system may comprise 1) at least one nanoparticle bonded to an oligonucleotide inhibitor strand which is hybridized with a catalytically active nucleic acid and 2) a compound bonded to at least one substrate molecule bonded to a therapeutically active substance (e.g., polynucleotides described herein), where the therapeutically active substance is released by the cleavage of the substrate molecule by the catalytically active nucleic acid.

In one embodiment, the NAVs may be formulated in a nanoparticle comprising an inner core comprising a non-cellular material and an outer surface comprising a cellular membrane. The cellular membrane may be derived from a cell or a membrane derived from a virus. As a non-limiting example, the nanoparticle may be made by the methods described in International Patent Publication No. WO2013052167, herein incorporated by reference in its entirety. As another non-limiting example, the nanoparticle described in International Patent Publication No. WO2013052167, herein incorporated by reference in its entirety, may be used to deliver the NAVs described herein.

In one embodiment, the NAVs may be formulated in porous nanoparticle-supported lipid bilayers (protocells). Protocells are described in International Patent Publication No. WO2013056132, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs described herein may be formulated in polymeric nanoparticles as described in or made by the methods described in U.S. Pat. Nos. 8,420,123 and 8,518,963 and European Patent No. EP2073848B1, the contents of each of which are herein incorporated by reference in their entirety. As a non-limiting example, the polymeric nanoparticle may have a high glass transition temperature such as the nanoparticles described in or nanoparticles made by the methods described in U.S. Pat. No. 8,518,963, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the polymer nanoparticle for oral and parenteral formulations may be made by the methods described in European Patent No. EP2073848B1, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the NAVs described herein may be formulated in nanoparticles used in imaging. The nanoparticles may be liposome nanoparticles such as those described in US Patent Publication No US20130129636, herein incorporated by reference in its entirety. As a non-limiting example, the liposome may comprise gadolinium(III)2-{4,7-bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amido-methyl]-1,4,7,10-tetra-azacyclododec-1-yl}-acetic acid and a neutral, fully saturated phospholipid component (see e.g., US Patent Publication No US20130129636, the contents of which is herein incorporated by reference in its entirety).

In one embodiment, the nanoparticles which may be used in the present invention are formed by the methods described in U.S. Patent Application No. US20130130348, the contents of which is herein incorporated by reference in its entirety.

The nanoparticles of the present invention may further include nutrients such as, but not limited to, those which deficiencies can lead to health hazards from anemia to neural tube defects (see e.g, the nanoparticles described in International Patent Publication No WO2013072929, the contents of which is herein incorporated by reference in its entirety). As a non-limiting example, the nutrient may be iron in the form of ferrous, ferric salts or elemental iron, iodine, folic acid, vitamins or micronutrients.

In one embodiment, the NAVs of the present invention may be formulated in a swellable nanoparticle. The swellable nanoparticle may be, but is not limited to, those described in U.S. Pat. No. 8,440,231, the contents of which is herein incorporated by reference in its entirety. As a non-limiting embodiment, the swellable nanoparticle may be used for delivery of the NAVs of the present invention to the pulmonary system (see e.g., U.S. Pat. No. 8,440,231, the contents of which is herein incorporated by reference in its entirety).

The NAVs of the present invention may be formulated in polyanhydride nanoparticles such as, but not limited to, those described in U.S. Pat. No. 8,449,916, the contents of which is herein incorporated by reference in its entirety.

The nanoparticles and microparticles of the present invention may be geometrically engineered to modulate macrophage and/or the immune response. In one aspect, the geometrically engineered particles may have varied shapes, sizes and/or surface charges in order to incorporated the polynucleotides of the present invention for targeted delivery such as, but not limited to, pulmonary delivery (see e.g., International Publication No WO2013082111, the contents of which is herein incorporated by reference in its entirety). Other physical features the geometrically engineering particles may have include, but are not limited to, fenestrations, angled arms, asymmetry and surface roughness, charge which can alter the interactions with cells and tissues. As a non-limiting example, nanoparticles of the present invention may be made by the methods described in International Publication No WO2013082111, the contents of which is herein incorporated by reference in its entirety.

In one embodiment, the nanoparticles of the present invention may be water soluble nanoparticles such as, but not limited to, those described in International Publication No. WO2013090601, the contents of which is herein incorporated by reference in its entirety. The nanoparticles may be inorganic nanoparticles which have a compact and zwitterionic ligand in order to exhibit good water solubility. The nanoparticles may also have small hydrodynamic diameters (HD), stability with respect to time, pH, and salinity and a low level of non-specific protein binding.

In one embodiment the nanoparticles of the present invention may be developed by the methods described in US Patent Publication No. US20130172406, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the nanoparticles of the present invention are stealth nanoparticles or target-specific stealth nanoparticles such as, but not limited to, those described in US Patent Publication No. US20130172406; the contents of which is herein incorporated by reference in its entirety. The nanoparticles of the present invention may be made by the methods described in US Patent Publication No. US20130172406, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the stealth or target-specific stealth nanoparticles may comprise a polymeric matrix. The polymeric matrix may comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polyesters, polyanhydrides, polyethers, polyurethanes, polymethacrylates, polyacrylates, polycyanoacrylates or combinations thereof.

In one embodiment, the nanoparticle may be a nanoparticle-nucleic acid hybrid structure having a high density nucleic acid layer. As a non-limiting example, the nanoparticle-nucleic acid hybrid structure may made by the methods described in US Patent Publication No. US20130171646, the contents of which are herein incorporated by reference in its entirety. The nanoparticle may comprise a nucleic acid such as, but not limited to, polynucleotides described herein and/or known in the art.

At least one of the nanoparticles of the present invention may be embedded in in the core a nanostructure or coated with a low density porous 3-D structure or coating which is capable of carrying or associating with at least one payload within or on the surface of the nanostructure. Non-limiting examples of the nanostructures comprising at least one nanoparticle are described in International Patent Publication No. WO2013123523, the contents of which are herein incorporated by reference in its entirety.

Polymers, Biodegradable Nanoparticles, and Core-Shell Nanoparticles

The NAVs of the invention can be formulated using natural and/or synthetic polymers. Non-limiting examples of polymers which may be used for delivery include, but are not limited to, DYNAMIC POLYCONJUGATE® (Arrowhead Research Corp., Pasadena, Calif.) formulations from MIRUS® Bio (Madison, Wis.) and Roche Madison (Madison, Wis.), PHASERX™ polymer formulations such as, without limitation, SMARTT POLYMER TECHNOLOGY™ (PHASERX®, Seattle, Wash.), DMRI/DOPE, poloxamer, VAXFECTIN® adjuvant from Vical (San Diego, Calif.), chitosan, cyclodextrin from Calando Pharmaceuticals (Pasadena, Calif.), dendrimers and poly(lactic-co-glycolic acid) (PLGA) polymers. RONDEL™ (RNAi/Oligonucleotide Nanoparticle Delivery) polymers (Arrowhead Research Corporation, Pasadena, Calif.) and pH responsive co-block polymers such as, but not limited to, PHASERX® (Seattle, Wash.).

A non-limiting example of chitosan formulation includes a core of positively charged chitosan and an outer portion of negatively charged substrate (U.S. Pub. No. 20120258176; herein incorporated by reference in its entirety). Chitosan includes, but is not limited to N-trimethyl chitosan, mono-N-carboxymethyl chitosan (MCC), N-palmitoyl chitosan (NPCS), EDTA-chitosan, low molecular weight chitosan, chitosan derivatives, or combinations thereof.

In one embodiment, the polymers used in the present invention have undergone processing to reduce and/or inhibit the attachement of unwanted substances such as, but not limited to, bacteria, to the surface of the polymer. The polymer may be processed by methods known and/or described in the art and/or described in International Pub. No. WO2012150467, herein incorporated by reference in its entirety.

A non-limiting example of PLGA formulations include, but are not limited to, PLGA injectable depots (e.g., ELIGARD® which is formed by dissolving PLGA in 66% N-methyl-2-pyrrolidone (NMP) and the remainder being aqueous solvent and leuprolide. Once injected, the PLGA and leuprolide peptide precipitates into the subcutaneous space).

Many of these polymer approaches have demonstrated efficacy in delivering oligonucleotides in vivo into the cell cytoplasm (reviewed in deFougerolles Hum Gene Ther. 2008 19:125-132; herein incorporated by reference in its entirety). Two polymer approaches that have yielded robust in vivo delivery of nucleic acids, in this case with small interfering RNA (siRNA), are dynamic polyconjugates and cyclodextrin-based nanoparticles (see e.g., US Patent Publication No. US20130156721, herein incorporated by reference in its entirety). The first of these delivery approaches uses dynamic polyconjugates and has been shown in vivo in mice to effectively deliver siRNA and silence endogenous target mRNA in hepatocytes (Rozema et al., Proc Natl Acad Sci USA. 2007 104:12982-12887; herein incorporated by reference in its entirety). This particular approach is a multicomponent polymer system whose key features include a membrane-active polymer to which nucleic acid, in this case siRNA, is covalently coupled via a disulfide bond and where both PEG (for charge masking) and N-acetylgalactosamine (for hepatocyte targeting) groups are linked via pH-sensitive bonds (Rozema et al., Proc Natl Acad Sci U.S.A. 2007 104:12982-12887; herein incorporated by reference in its entirety). On binding to the hepatocyte and entry into the endosome, the polymer complex disassembles in the low-pH environment, with the polymer exposing its positive charge, leading to endosomal escape and cytoplasmic release of the siRNA from the polymer. Through replacement of the N-acetylgalactosamine group with a mannose group, it was shown one could alter targeting from asialoglycoprotein receptor-expressing hepatocytes to sinusoidal endothelium and Kupffer cells. Another polymer approach involves using transferrin-targeted cyclodextrin-containing polycation nanoparticles. These nanoparticles have demonstrated targeted silencing of the EWS-FLI1 gene product in transferrin receptor-expressing Ewing's sarcoma tumor cells (Hu-Lieskovan et al., Cancer Res.2005 65: 8984-8982; herein incorporated by reference in its entirety) and siRNA formulated in these nanoparticles was well tolerated in non-human primates (Heidel et al., Proc Natl Acad Sci USA 2007 104:5715-21; herein incorporated by reference in its entirety). Both of these delivery strategies incorporate rational approaches using both targeted delivery and endosomal escape mechanisms.

The polymer formulation can permit the sustained or delayed release of polynucleotides (e.g., following intramuscular or subcutaneous injection). The altered release profile for the polynucleotide can result in, for example, translation of an encoded protein over an extended period of time. The polymer formulation may also be used to increase the stability of the polynucleotide. Biodegradable polymers have been previously used to protect nucleic acids other than polynucleotide from degradation and been shown to result in sustained release of payloads in vivo (Rozema et al., Proc Natl Acad Sci U.S.A. 2007 104:12982-12887; Sullivan et al., Expert Opin Drug Deliv. 2010 7:1433-1446; Convertine et al., Biomacromolecules. 2010 Oct. 1; Chu et al., Acc Chem Res. 2012 Jan. 13; Manganiello et al., Biomaterials. 2012 33:2301-2309; Benoit et al., Biomacromolecules. 2011 12:2708-2714; Singha et al., Nucleic Acid Ther. 2011 2:133-147; deFougerolles Hum Gene Ther. 2008 19:125-132; Schaffert and Wagner, Gene Ther. 2008 16:1131-1138; Chaturvedi et al., Expert Opin Drug Deliv. 2011 8:1455-1468; Davis, Mol Pharm. 2009 6:659-668; Davis, Nature 2010 464:1067-1070; each of which is herein incorporated by reference in its entirety).

In one embodiment, the NAV pharmaceutical compositions may be sustained release formulations. In a further embodiment, the sustained release formulations may be for subcutaneous delivery. Sustained release formulations may include, but are not limited to, PLGA microspheres, ethylene vinyl acetate (EVAc), poloxamer, GELSITE® (Nanotherapeutics, Inc. Alachua, Fla.), HYLENEX® (Halozyme Therapeutics, San Diego Calif.), surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, Ga.), TISSELL® (Baxter International, Inc Deerfield, Ill.), PEG-based sealants, and COSEAL® (Baxter International, Inc Deerfield, Ill.).

As a non-limiting example NAVs may be formulated in PLGA microspheres by preparing the PLGA microspheres with tunable release rates (e.g., days and weeks) and encapsulating the modified mRNA in the PLGA microspheres while maintaining the integrity of the modified mRNA during the encapsulation process. EVAc are non-biodegradeable, biocompatible polymers which are used extensively in pre-clinical sustained release implant applications (e.g., extended release products Ocusert a pilocarpine ophthalmic insert for glaucoma or progestasert a sustained release progesterone intrauterine deivce; transdermal delivery systems Testoderm, Duragesic and Selegiline; catheters). Poloxamer F-407 NF is a hydrophilic, non-ionic surfactant triblock copolymer of polyoxyethylene-polyoxypropylene-polyoxyethylene having a low viscosity at temperatures less than 5° C. and forms a solid gel at temperatures greater than 15° C. PEG-based surgical sealants comprise two synthetic PEG components mixed in a delivery device which can be prepared in one minute, seals in 3 minutes and is reabsorbed within 30 days. GELSITE® and natural polymers are capable of in-situ gelation at the site of administration. They have been shown to interact with protein and peptide therapeutic candidates through ionic ineraction to provide a stabilizing effect.

Polymer formulations can also be selectively targeted through expression of different ligands as exemplified by, but not limited by, folate, transferrin, and N-acetylgalactosamine (GalNAc) (Benoit et al., Biomacromolecules. 2011 12:2708-2714; Rozema et al., Proc Natl Acad Sci U.S.A. 2007 104:12982-12887; Davis, Mol Pharm. 2009 6:659-668; Davis, Nature 2010 464:1067-1070; each of which is herein incorporated by reference in its entirety).

The NAVs of the invention may be formulated with or in a polymeric compound. The polymer may include at least one polymer such as, but not limited to, polyethenes, polyethylene glycol (PEG), poly(l-lysine)(PLL), PEG grafted to PLL, cationic lipopolymer, biodegradable cationic lipopolymer, polyethyleneimine (PEI), cross-linked branched poly(alkylene imines), a polyamine derivative, a modified poloxamer, a biodegradable polymer, elastic biodegradable polymer, biodegradable block copolymer, biodegradable random copolymer, biodegradable polyester copolymer, biodegradable polyester block copolymer, biodegradable polyester block random copolymer, multiblock copolymers, linear biodegradable copolymer, poly[α-(4-aminobutyl)-L-glycolic acid) (PAGA), biodegradable cross-linked cationic multi-block copolymers, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), acrylic polymers, amine-containing polymers, dextran polymers, dextran polymer derivatives or or combinations thereof.

As a non-limiting example, the NAVs of the invention may be formulated with the polymeric compound of PEG grafted with PLL as described in U.S. Pat. No. 6,177,274; herein incorporated by reference in its entirety. The formulation may be used for transfecting cells in vitro or for in vivo delivery of polynucleotides. In another example, the polynucleotide may be suspended in a solution or medium with a cationic polymer, in a dry pharmaceutical composition or in a solution that is capable of being dried as described in U.S. Pub. Nos. 20090042829 and 20090042825; each of which are herein incorporated by reference in their entireties.

As another non-limiting example the NAVs of the invention may be formulated with a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and U.S. Pat. No. 8,236,330, herein incorporated by reference in their entireties) or PLGA-PEG-PLGA block copolymers (See U.S. Pat. No. 6,004,573, herein incorporated by reference in its entirety). As a non-limiting example, the NAVs of the invention may be formulated with a diblock copolymer of PEG and PLA or PEG and PLGA (see U.S. Pat. No. 8,246,968, herein incorporated by reference in its entirety).

A polyamine derivative may be used to deliver nucleic acids or to treat and/or prevent a disease or to be included in an implantable or injectable device (U.S. Pub. No. 20100260817 (now U.S. Pat. No. 8,460,696) the contents of each of which is herein incorporated by reference in its entirety). As a non-limiting example, a pharmaceutical composition may include the NAV and the polyamine derivative described in U.S. Pub. No. 20100260817 (now U.S. Pat. No. 8,460,696; the contents of which are incorporated herein by reference in its entirety. As a non-limiting example the NAVs of the present invention may be delivered using a polyaminde polymer such as, but not limited to, a polymer comprising a 1,3-dipolar addition polymer prepared by combining a carbohydrate diazide monomer with a dilkyne unite comprising oligoamines (U.S. Pat. No. 8,236,280; herein incorporated by reference in its entirety).

The NAVs of the invention may be formulated with at least one acrylic polymer. Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof.

In one embodiment, the NAVs of the present invention may be formulated with at least one polymer and/or derivatives thereof described in International Publication Nos. WO2011115862, WO2012082574 and WO2012068187 and U.S. Pub. No. 20120283427, each of which are herein incorporated by reference in their entireties.

In another embodiment, the NAVs of the present invention may be formulated with a polymer of formula Z as described in WO2011115862, herein incorporated by reference in its entirety. In yet another embodiment, the NAVs may be formulated with a polymer of formula Z, Z′ or Z″ as described in International Pub. Nos. WO2012082574 or WO2012068187 and U.S. Pub. No. 2012028342, each of which are herein incorporated by reference in their entireties. The polymers formulated with the modified RNA of the present invention may be synthesized by the methods described in International Pub. Nos. WO2012082574 or WO2012068187, each of which are herein incorporated by reference in their entireties.

The NAVs of the invention may be formulated with at least one acrylic polymer. Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof.

Formulations of NAVs of the invention may include at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly(amidoamine) dendrimers, poly(amine-co-esters) or combinations thereof. As a non-limiting example, the poly(amine-co-esters) may be the polymers described in and/or made by the methods described in International Publication No WO2013082529, the contents of which are herein incorporated by reference in its entirety.

For example, the NAVs of the invention may be formulated in a pharmaceutical compound including a poly(alkylene imine), a biodegradable cationic lipopolymer, a biodegradable block copolymer, a biodegradable polymer, or a biodegradable random copolymer, a biodegradable polyester block copolymer, a biodegradable polyester polymer, a biodegradable polyester random copolymer, a linear biodegradable copolymer, PAGA, a biodegradable cross-linked cationic multi-block copolymer or combinations thereof. The biodegradable cationic lipopolymer may be made by methods known in the art and/or described in U.S. Pat. No. 6,696,038, U.S. App. Nos. 20030073619 and 20040142474 each of which is herein incorporated by reference in their entireties. The poly(alkylene imine) may be made using methods known in the art and/or as described in U.S. Pub. No. 20100004315, herein incorporated by reference in its entirety. The biodegradabale polymer, biodegradable block copolymer, the biodegradable random copolymer, biodegradable polyester block copolymer, biodegradable polyester polymer, or biodegradable polyester random copolymer may be made using methods known in the art and/or as described in U.S. Pat. Nos. 6,517,869 and 6,267,987, the contents of which are each incorporated herein by reference in their entirety. The linear biodegradable copolymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,652,886. The PAGA polymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,217,912 herein incorporated by reference in its entirety. The PAGA polymer may be copolymerized to form a copolymer or block copolymer with polymers such as but not limited to, poly-L-lysine, polyargine, polyornithine, histones, avidin, protamines, polylactides and poly(lactide-co-glycolides). The biodegradable cross-linked cationic multi-block copolymers may be made my methods known in the art and/or as described in U.S. Pat. Nos. 8,057,821, 8,444,992 or U.S. Pub. No. 2012009145 each of which are herein incorporated by reference in their entireties. For example, the multi-block copolymers may be synthesized using linear polyethyleneimine (LPEI) blocks which have distinct patterns as compared to branched polyethyleneimines. Further, the composition or pharmaceutical composition may be made by the methods known in the art, described herein, or as described in U.S. Pub. No. 20100004315 or U.S. Pat. Nos. 6,267,987 and 6,217,912 each of which are herein incorporated by reference in their entireties.

The NAVs of the invention may be formulated with at least one degradable polyester which may contain polycationic side chains. Degradeable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof. In another embodiment, the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.

The NAVs of the invention may be formulated with at least one crosslinkable polyester. Crosslinkable polyesters include those known in the art and described in US Pub. No. 20120269761, the contents of which is herein incorporated by reference in its entirety.

The NAVs of the invention may be formulated in or with at least one cyclodextrin polymer. Cyclodextrin polymers and methods of making cyclodextrin polymers include those known in the art and described in US Pub. No. 20130184453, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs of the invention may be formulated in or with at least one crosslinked cation-binding polymers. Crosslinked cation-binding polymers and methods of making crosslinked cation-binding polymers include those known in the art and described in International Patent Publication No. WO2013106072, WO2013106073 and WO2013106086, the contents of each of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs of the invention may be formulated in or with at least one branched polymer. Branched polymers and methods of making branched polymers include those known in the art and described in International Patent Publication No. WO2013113071, the contents of each of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs of the invention may be formulated in or with at least PEGylated albumin polymer. PEGylated albumin polymer and methods of making PEGylated albumin polymer include those known in the art and described in US Patent Publication No. US20130231287, the contents of each of which are herein incorporated by reference in its entirety.

In one embodiment, the polymers described herein may be conjugated to a lipid-terminating PEG. As a non-limiting example, PLGA may be conjugated to a lipid-terminating PEG forming PLGA-DSPE-PEG. As another non-limiting example, PEG conjugates for use with the present invention are described in International Publication No. WO2008103276, herein incorporated by reference in its entirety. The polymers may be conjugated using a ligand conjugate such as, but not limited to, the conjugates described in U.S. Pat. No. 8,273,363, herein incorporated by reference in its entirety.

In one embodiment, the NAVs disclosed herein may be mixed with the PEGs or the sodium phosphate/sodium carbonate solution prior to administration.

In another embodiment, a polynucleotides encoding a protein of interest may be mixed with the PEGs and also mixed with the sodium phosphate/sodium carbonate solution.

In yet another embodiment, polynucleotides encoding a protein of interest may be mixed with the PEGs and a polynucleotides encoding a second protein of interest may be mixed with the sodium phosphate/sodium carbonate solution.

In one embodiment, the NAVs described herein may be conjugated with another compound. Non-limiting examples of conjugates are described in U.S. Pat. Nos. 7,964,578 and 7,833,992, each of which are herein incorporated by reference in their entireties. In another embodiment, the NAVs of the present invention may be conjugated with conjugates of formula 1-122 as described in U.S. Pat. Nos. 7,964,578 and 7,833,992, each of which are herein incorporated by reference in their entireties. The NAVs described herein may be conjugated with a metal such as, but not limited to, gold. (See e.g., Giljohann et al. Journ. Amer. Chem. Soc. 2009 131(6): 2072-2073; herein incorporated by reference in its entirety). In another embodiment, the NAVs described herein may be conjugated and/or encapsulated in gold-nanoparticles. (International Pub. No. WO201216269 and U.S. Pub. No. 20120302940 and US20130177523; the contents of each of which is herein incorporated by reference in its entirety).

As described in U.S. Pub. No. 20100004313, herein incorporated by reference in its entirety, a gene delivery composition may include a nucleotide sequence and a poloxamer. For example, the NAVs of the present inveition may be used in a gene delivery composition with the poloxamer described in U.S. Pub. No. 20100004313, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the polymer formulation of the present invention may be stabilized by contacting the polymer formulation, which may include a cationic carrier, with a cationic lipopolymer which may be covalently linked to cholesterol and polyethylene glycol groups. The polymer formulation may be contacted with a cationic lipopolymer using the methods described in U.S. Pub. No. 20090042829 herein incorporated by reference in its entirety. The cationic carrier may include, but is not limited to, polyethylenimine, poly(trimethylenimine), poly(tetramethylenimine), polypropylenimine, aminoglycoside-polyamine, dideoxy-diamino-b-cyclodextrin, spermine, spermidine, poly(2-dimethylamino)ethyl methacrylate, poly(lysine), poly(histidine), poly(arginine), cationized gelatin, dendrimers, chitosan, 1,2-Dioleoyl-3-Trimethylammonium-Propane(DOTAP), N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1-[2-(oleoyloxy)ethyl]-2-oleyl-3-(2-hydroxyethyl)imidazolinium chloride (DOTIM), 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), 3B-[N-(N′,N′-Dimethylaminoethane)-carbamoyl]Cholesterol Hydrochloride (DC-Cholesterol HCl) diheptadecylamidoglycyl spermidine (DOGS), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE), N,N-dioleyl-N,N-dimethylammonium chloride DODAC) and combinations thereof. As a non-limiting example, the NAVs may be formulated with a cationic lipopolymer such as those described in U.S. Patent Application No. 20130065942, the contents of which are herein incorporated by reference in its entirety.

The NAVs of the invention may be formulated in a polyplex of one or more polymers (See e.g., U.S. Pat. No. 8,501,478, U.S. Pub. No. 20120237565 and 20120270927 and 20130149783 and International Patent Pub. No. WO2013090861; the contents of each of which is herein incorporated by reference in its entirety). As a non-limiting example, the polyplex may be formed using the noval alpha-aminoamidine polymers described in International Publication No. WO2013090861, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the polyplex may be formed using the click polymers described in U.S. Pat. No. 8,501,478, the contents of which is herein incorporated by reference in its entirety.

In one embodiment, the polyplex comprises two or more cationic polymers. The catioinic polymer may comprise a poly(ethylene imine) (PEI) such as linear PEI. In another embodiment, the polyplex comprises p(TETA/CBA) its PEGylated analog p(TETA/CBA)-g-PEG2k and mixtures thereof (see e.g., US Patent Publication No. US20130149783, the contents of which are herein incorporated by reference in its entirety.

The NAVs of the invention can also be formulated as a nanoparticle using a combination of polymers, lipids, and/or other biodegradable agents, such as, but not limited to, calcium phosphate. Components may be combined in a core-shell, hybrid, and/or layer-by-layer architecture, to allow for fine-tuning of the nanoparticle so to delivery of the NAV, may be enhanced (Wang et al., Nat Mater. 2006 5:791-796; Fuller et al., Biomaterials. 2008 29:1526-1532; DeKoker et al., Adv Drug Deliv Rev. 2011 63:748-761; Endres et al., Biomaterials. 2011 32:7721-7731; Su et al., Mol Pharm. 2011 Jun. 6; 8(3):774-87; herein incorporated by reference in its entirety). As a non-limiting example, the nanoparticle may comprise a plurality of polymers such as, but not limited to hydrophilic-hydrophobic polymers (e.g., PEG-PLGA), hydrophobic polymers (e.g., PEG) and/or hydrophilic polymers (International Pub. No. WO20120225129; the contents of which is herein incorporated by reference in its entirety).

As another non-limiting example the nanoparticle comprising hydrophilic polymers for the NAVs may be those described in or made by the methods described in International Patent Publication No. WO2013119936, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the biodegradable polymers which may be used in the present invention are poly(ether-anhydride) block copolymers. As a non-limiting example, the biodegradable polymers used herein may be a block copolymer as described in International Patent Publication No WO2006063249, herein incorporated by reference in its entirety, or made by the methods described in International Patent Publication No WO2006063249, herein incorporated by reference in its entirety.

In another embodiment, the biodegradable polymers which may be used in the present invention are alkyl and cycloalkyl terminated biodegradable lipids. As a non-limiting example, the alkyl and cycloalkyl terminated biodegradable lipids may be those described in International Publication No. WO2013086322 and/or made by the methods described in International Publication No. WO2013086322; the contents of which are herein incorporated by reference in its entirety.

In yet another embodiment, the biodegradable polymers which may be used in the present invention are cationic lipids having one or more biodegradable group located in a lipid moiety. As a non-limiting example, the biodegradable lipids may be those described in US Patent Publication No. US20130195920, the contents of which are herein incorporated by reference in its entirety.

Biodegradable calcium phosphate nanoparticles in combination with lipids and/or polymers have been shown to deliver polynucleotides in vivo. In one embodiment, a lipid coated calcium phosphate nanoparticle, which may also contain a targeting ligand such as anisamide, may be used to deliver the NAVof the present invention. For example, to effectively deliver siRNA in a mouse metastatic lung model a lipid coated calcium phosphate nanoparticle was used (Li et al., J Contr Rel. 2010 142: 416-421; Li et al., J Contr Rel. 2012 158:108-114; Yang et al., Mol Ther. 2012 20:609-615; herein incorporated by reference in its entirety). This delivery system combines both a targeted nanoparticle and a component to enhance the endosomal escape, calcium phosphate, in order to improve delivery of the siRNA.

In one embodiment, calcium phosphate with a PEG-polyanion block copolymer may be used to delivery NAVs (Kazikawa et al., J Contr Rel. 2004 97:345-356; Kazikawa et al., J Contr Rel. 2006 111:368-370; the contents of each of which are herein incorporated by reference in its entirety).

In one embodiment, a PEG-charge-conversional polymer (Pitella et al., Biomaterials. 2011 32:3106-3114; the contents of which are herein incorporated by reference in its entirety) may be used to form a nanoparticle to deliver the NAVs of the present invention. The PEG-charge-conversional polymer may improve upon the PEG-polyanion block copolymers by being cleaved into a polycation at acidic pH, thus enhancing endosomal escape.

In one embodiment, a polymer used in the present invention may be a pentablock polymer such as, but not limited to, the pentablock polymers described in International Patent Publication No. WO2013055331, herein incorporated by reference in its entirety. As a non-limiting example, the pentablock polymer comprises PGA-PCL-PEG-PCL-PGA, wherein PEG is polyethylene glycol, PCL is poly(E-caprolactone), PGA is poly(glycolic acid), and PLA is poly(lactic acid). As another non-limiting example, the pentablock polymer comprises PEG-PCL-PLA-PCL-PEG, wherein PEG is polyethylene glycol, PCL is poly(E-caprolactone), PGA is poly(glycolic acid), and PLA is poly(lactic acid).

In one embodiment, a polymer which may be used in the present invention comprises at least one diepoxide and at least one aminoglycoside (See e.g., International Patent Publication No. WO2013055971, the contents of which are herein incorporated by reference in its entirety). The diepoxide may be selected from, but is not limited to, 1,4 butanediol diglycidyl ether (1,4 B), 1,4-cyclohexanedimethanol diglycidyl ether (1,4 C), 4-vinylcyclohexene diepoxide (4VCD), ethyleneglycol diglycidyl ether (EDGE), glycerol diglycidyl ether (GDE), neopentylglycol diglycidyl ether (NPDGE), poly(ethyleneglycol) diglycidyl ether (PEGDE), poly(propyleneglycol) diglycidyl ether (PPGDE) and resorcinol diglycidyl ether (RDE). The aminoglycoside may be selected from, but is not limited to, streptomycin, neomycin, framycetin, paromomycin, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, astromicin, and apramycin. As a non-limiting example, the polymers may be made by the methods described in International Patent Publication No. WO2013055971, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, compositions comprising any of the polymers comprising at least one least one diepoxide and at least one aminoglycoside may be made by the methods described in International Patent Publication No. WO2013055971, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, a polymer which may be used in the present invention may be a cross-linked polymer. As a non-limiting example, the cross-linked polymers may be used to form a particle as described in U.S. Pat. No. 8,414,927, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the cross-linked polymer may be obtained by the methods described in US Patent Publication No. US20130172600, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, a polymer which may be used in the present invention may be a cross-linked polymer such as those described in U.S. Pat. No. 8,461,132, the contents of which are herein incorporated by reference in its entirety. As a non-limiting example, the cross-linked polymer may be used in a therapeutic composition for the treatment of a body tissue. The therapeutic composition may be administered to damaged tissue using various methods known in the art and/or described herein such as injection or catheterization.

In one embodiment, a polymer which may be used in the present invention may be a di-alphatic substituted pegylated lipid such as, but not limited to, those described in International Patent Publication No. WO2013049328, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, a block copolymer is PEG-PLGA-PEG (see e.g., the thermosensitive hydrogel (PEG-PLGA-PEG) was used as a TGF-beta1 gene delivery vehicle in Lee et al. Thermosensitive Hydrogel as a Tgf-β1 Gene Delivery Vehicle Enhances Diabetic Wound Healing. Pharmaceutical Research, 2003 20(12): 1995-2000; as a controlled gene delivery system in Li et al. Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel. Pharmaceutical Research 2003 20(6):884-888; and Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253; each of which is herein incorporated by reference in its entirety) may be used in the present invention. The present invention may be formulated with PEG-PLGA-PEG for administration such as, but not limited to, intramuscular and subcutaneous administration.

In another embodiment, the PEG-PLGA-PEG block copolymer is used in the present invention to develop a biodegradable sustained release system. In one aspect, the NAVs of the present invention are mixed with the block copolymer prior to administration. In another aspect, the NAVs of the present invention are co-administered with the block copolymer.

In one embodiment, the polymer used in the present invention may be a multi-functional polymer derivative such as, but not limited to, a multi-functional N-maleimidyl polymer derivatives as described in U.S. Pat. No. 8,454,946, the contents of which are herein incorporated by reference in its entirety.

The use of core-shell nanoparticles has additionally focused on a high-throughput approach to synthesize cationic cross-linked nanogel cores and various shells (Siegwart et al., Proc Natl Acad Sci U.S.A. 2011 108:12996-13001; the contents of which are herein incorporated by reference in its entirety). The complexation, delivery, and internalization of the polymeric nanoparticles can be precisely controlled by altering the chemical composition in both the core and shell components of the nanoparticle. For example, the core-shell nanoparticles may efficiently deliver siRNA to mouse hepatocytes after they covalently attach cholesterol to the nanoparticle.

In one embodiment, a hollow lipid core comprising a middle PLGA layer and an outer neutral lipid layer containg PEG may be used to delivery of the NAV of the present invention. As a non-limiting example, in mice bearing a luciferease-expressing tumor, it was determined that the lipid-polymer-lipid hybrid nanoparticle significantly suppressed luciferase expression, as compared to a conventional lipoplex (Shi et al, Angew Chem Int Ed. 2011 50:7027-7031; herein incorporated by reference in its entirety).

In one embodiment, the lipid nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the polynucleotides in the core.

Core-shell nanoparticles for use with the NAVs of the present invention are described and may be formed by the methods described in U.S. Pat. No. 8,313,777 or International Patent Publication No. WO2013124867, the contents of each of which are herein incorporated by reference in their entirety.

In one embodiment, the polymer used with the formulations described herein may be a modified polymer (such as, but not limited to, a modified polyacetal) as described in International Publication No. WO2011120053, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the formulation may be a polymeric carrier cargo complex comprising a polymeric carrier and at least one nucleic acid molecule. Non-limiting examples of polymeric carrier cargo complexes are described in International Patent Publications Nos. WO2013113326, WO2013113501, WO2013113325, WO2013113502 and WO2013113736 and European Patent Publication No. EP2623121, the contents of each of which are herein incorporated by reference in their entireties. In one aspect the polymeric carrier cargo complexes may comprise a negatively charged nucleic acid molecule such as, but not limited to, those described in International Patent Publication Nos. WO2013113325 and WO2013113502, the contents of each of which are herein incorporated by reference in its entirety.

In one embodiment, a pharmaceutical composition may comprise NAVs of the invention and a polymeric carrier cargo complex. The polynucleotides may encode a protein of interest such as, but not limited to, an antigen from a pathogen associated with infectious disease, an antigen associated with allergy or allergic disease, an antigen associated with autoimmune disease or an antigen assocated with cancer or tumour disease (See e.g., the antigens described in International Patent Publications Nos. WO2013113326, WO2013113501, WO2013113325, WO2013113502 and WO2013113736 and European Patent Publication No. EP2623121, the contents of each of which are herein incorporated by reference in their entireties).

As a non-limiting example, the core-shell nanoparticle may be used to treat an eye disease or disorder (See e.g. US Publication No. 20120321719, the contents of which are herein incorporated by reference in its entirety).

In one embodiment, the polymer used with the formulations described herein may be a modified polymer (such as, but not limited to, a modified polyacetal) as described in International Publication No. WO2011120053, the contents of which are herein incorporated by reference in its entirety.

Peptides and Proteins

The NAVs of the invention can be formulated with peptides and/or proteins in order to increase transfection of cells by the polynucleotide. In one embodiment, peptides such as, but not limited to, cell penetrating peptides and proteins and peptides that enable intracellular delivery may be used to deliver pharmaceutical formulations. A non-limiting example of a cell penetrating peptide which may be used with the pharmaceutical formulations of the present invention includes a cell-penetrating peptide sequence attached to polycations that facilitates delivery to the intracellular space, e.g., HIV-derived TAT peptide, penetratins, transportans, or hCT derived cell-penetrating peptides (see, e.g., Caron et al., Mol. Ther. 3(3):310-8 (2001); Langel, Cell-Penetrating Peptides: Processes and Applications (CRC Press, Boca Raton Fla., 2002); El-Andaloussi et al., Curr. Pharm. Des. 11(28):3597-611 (2003); and Deshayes et al., Cell. Mol. Life Sci. 62(16):1839-49 (2005), all of which are incorporated herein by reference in their entirety). The compositions can also be formulated to include a cell penetrating agent, e.g., liposomes, which enhance delivery of the compositions to the intracellular space. NAVs of the invention may be complexed to peptides and/or proteins such as, but not limited to, peptides and/or proteins from Aileron Therapeutics (Cambridge, Mass.) and Permeon Biologics (Cambridge, Mass.) in order to enable intracellular delivery (Cronican et al., ACS Chem. Biol. 2010 5:747-752; McNaughton et al., Proc. Natl. Acad. Sci. USA 2009 106:6111-6116; Sawyer, Chem Biol Drug Des. 2009 73:3-6; Verdine and Hilinski, Methods Enzymol. 2012; 503:3-33; all of which are herein incorporated by reference in its entirety).

In one embodiment, the cell-penetrating polypeptide may comprise a first domain and a second domain. The first domain may comprise a supercharged polypeptide. The second domain may comprise a protein-binding partner. As used herein, “protein-binding partner” includes, but are not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides. The cell-penetrating polypeptide may further comprise an intracellular binding partner for the protein-binding partner. The cell-penetrating polypeptide may be capable of being secreted from a cell where the polynucleotide may be introduced.

Formulations of the including peptides or proteins may be used to increase cell transfection by the NAV, alter the biodistribution of the polynucleotide (e.g., by targeting specific tissues or cell types), and/or increase the translation of encoded protein. (See e.g., International Pub. No. WO2012110636 and WO2013123298; the contents of which are herein incorporated by reference in its entirety).

In one embodiment, the cell penetrating peptide may be, but is not limited to, those described in US Patent Publication No US20130129726, US20130137644 and US20130164219, each of which is herein incorporated by reference in its entirety.

Cells

The NAVs of the invention can be transfected ex vivo into cells, which are subsequently transplanted into a subject.

As one non-limiting example, a sample of blood from a patient or subject may be treated with an antigen or adjuvant or both where one or more are encoded by the NAVs of the invention to activate the PBMC population. This activated sample or a subset of specific cells may then be given back to the donor patient thereby activating the immune system. This activated PBMC vaccine may be designed using any of the NAVs of the present disclosure.

As non-limiting examples, the pharmaceutical compositions may include red blood cells to deliver modified RNA to liver and myeloid cells, virosomes to deliver modified RNA in virus-like particles (VLPs), and electroporated cells such as, but not limited to, from MAXCYTE® (Gaithersburg, Md.) and from ERYTECH® (Lyon, France) to deliver modified RNA. Examples of use of red blood cells, viral particles and electroporated cells to deliver payloads other than polynucleotides have been documented (Godfrin et al., Expert Opin Biol Ther. 2012 12:127-133; Fang et al., Expert Opin Biol Ther. 2012 12:385-389; Hu et al., Proc Natl Acad Sci U.S.A. 2011 108:10980-10985; Lund et al., Pharm Res. 2010 27:400-420; Huckriede et al., J Liposome Res. 2007; 17:39-47; Cusi, Hum Vaccin. 2006 2:1-7; de Jonge et al., Gene Ther. 2006 13:400-411; all of which are herein incorporated by reference in its entirety).

The NAVs may be delivered in synthetic VLPs synthesized by the methods described in International Pub No. WO2011085231 and WO2013116656 and US Pub No. 20110171248, the contents of each of which are herein incorporated by reference in their entireties.

Cell-based formulations of the NAVs of the invention may be used to ensure cell transfection (e.g., in the cellular carrier), alter the biodistribution of the polynucleotide (e.g., by targeting the cell carrier to specific tissues or cell types), and/or increase the translation of encoded protein.

Introduction Into Cells

A variety of methods are known in the art and suitable for introduction of nucleic acid into a cell, including viral and non-viral mediated techniques and any of these may be used to introduce the NAVs of the present invention. Examples of typical non-viral mediated techniques include, but are not limited to, electroporation, calcium phosphate mediated transfer, nucleofection, sonoporation, heat shock, magnetofection, liposome mediated transfer, microinjection, microprojectile mediated transfer (nanoparticles), cationic polymer mediated transfer (DEAE-dextran, polyethylenimine, polyethylene glycol (PEG) and the like) or cell fusion.

The technique of sonoporation, or cellular sonication, is the use of sound (e.g., ultrasonic frequencies) for modifying the permeability of the cell plasma membrane. Sonoporation methods are known to those in the art and are used to deliver nucleic acids in vivo (Yoon and Park, Expert Opin Drug Deliv. 2010 7:321-330; Postema and Gilja, Curr Pharm Biotechnol. 2007 8:355-361; Newman and Bettinger, Gene Ther. 2007 14:465-475; all herein incorporated by reference in their entirety). Sonoporation methods are known in the art and are also taught for example as it relates to bacteria in US Patent Publication 20100196983 and as it relates to other cell types in, for example, US Patent Publication 20100009424, each of which are incorporated herein by reference in their entirety.

Electroporation techniques are also well known in the art and are used to deliver nucleic acids in vivo and clinically (Andre et al., Curr Gene Ther. 2010 10:267-280; Chiarella et al., Curr Gene Ther. 2010 10:281-286; Hojman, Curr Gene Ther. 2010 10:128-138; all herein incorporated by reference in their entirety). Electroporation devices are sold by many companies worldwide including, but not limited to BTX® Instruments (Holliston, Mass.) (e.g., the AgilePulse In Vivo System) and Inovio (Blue Bell, Pa.) (e.g., Inovio SP-5P intramuscular delivery device or the CELLECTRA® 3000 intradermal delivery device). In one embodiment, NAVs may be delivered by electroporation as described in Example 9.

Micro-Organ

The NAVs may be contained in a micro-organ which can then express an encoded polypeptide of interest in a long-lasting therapeutic formulation. In one aspect, the micro-organ may comprise a vector comprising a nucleic acid sequence (e.g., a polynucleotides of the present invention) encoding a polypeptide of interest, operably linked to one or more regulatory sequences. As a non-limiting example, the long-lasting therapeutic micro-organ used with the present invention may be those described in U.S. Pat. No. 845,948, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the micro-organ may be used to maintain a desired level of a polypeptide of interest for a sustained period of time (e.g., maintaining physiological hemoglobin levels as described in U.S. Pat. No. 845,948, the contents of which are herein incorporated by reference in its entirety).

The micro-organ may be able to produce the polypeptide of interest for at least a day, at least two days, at least three days, at least four days, at least five days, at least six days, a least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 3 weeks, at least 1 month and/or at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months or greater than 6 months.

In one embodiment, the micro-organ may have a diameter of at least 0.5 mm to at least 20 mm such as, but not limited to, at least 0.5 mm, at least 1 mm, at least 1.5 mm, at least 2 mm, at least 2.5 mm, at least 3 mm, at least 3.5 mm, at least 4 mm, at least 4.5 mm, at least 5 mm, at least 5.5 mm, at least 6 mm, at least 6.5 mm, at least 7 mm, at least 7.5 mm, at least 8 mm, at least 8.5 mm, at least 9 mm, at least 9.5 mm, at least 10 mm, at least 10.5 mm, at least 11 mm, at least 11.5 mm, at least 12 mm, at least 12.5 mm, at least 13 mm, at least 13.5 mm, at least 14 mm, at least 14.5 mm, at least 15 mm, at least 15.5. mm, at least 16 mm, at least 16.5 mm, at least 17 mm, at least 17.5 mm, at least 18 mm, at least 18.5 mm, at least 19 mm, at least 19.5 mm or at least 20 mm. In another embodiment, the micro-organ may have a diameter of 0.5-2.5 mm, 1-2.5 mm, 1.5-2.5 mm, 0.5-3 mm, 1-3 mm, 1.5-3 mm, 0.5-3.5 mm, 1-3.5 mm, 1.5-3.5 mm, 0.5-4 mm, 1-4 mm, 1.5-4 mm, 2-4 mm, 0.5-5 mm, 1-5 mm, 1.5-5 mm, 2-5 mm, 2.5-5 mm, 3-5 mm, 0.5-6 mm, 1-6 mm, 1.5-6 mm, 2-6 mm, 2.5-6 mm, 3-6 mm, 3.5-6 mm, 4-6 mm, 0.5-7 mm, 1-7 mm, 1.5-7 mm, 2-7 mm, 2.5-7 mm, 3-7 mm, 3.5-7 mm, 4-7 mm, 4.5-7 mm, 5-7 mm, 0.5-8 mm, 1-8 mm, 1.5-8 mm, 2-8 mm, 2.5-8 mm, 3-8 mm, 3.5-8 mm, 4-8 mm, 4.5-8 mm, 5-8 mm, 5.5-8 mm, 6-8 mm, 0.5-9 mm, 1-9 mm, 1.5-9 mm, 2-9 mm, 2.5-9 mm, 3-9 mm, 3.5-9 mm, 4-9 mm, 4.5-9 mm, 5-9 mm, 5.5-9 mm, 6-9 mm, 6.5-9 mm, 7-9 mm, 0.5-10 mm, 1-10 mm, 1.5-10 mm, 2-10 mm, 2.5-10 mm, 3-10 mm, 3.5-10 mm, 4-10 mm, 4.5-10 mm, 5-10 mm, 5.5-10 mm, 6-10 mm, 6.5-10 mm, 7-10 mm, 7.5-10 nm or 8-10 nm.

In one embodiment, the micro-organ may have a length of at least 2 mm to at least 150 mm such as, but not limited to, at least 2 mm, at least 3 mm, at least 4 mm, at least 5 mm, at least 6 mm, at least 7 mm, at least 8 mm, at least 9 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least 30 mm, at least 35 mm, at least 40 mm, at least 45 mm, at least 50 mm, at least 55 mm, at least 60 mm, at least 65 mm, at least 70 mm, at least 75 mm, at least 80 mm, at least 85 mm, at least 90 mm, at least 95 mm, at least 100 mm, at least 105 mm, at least 110 mm, at least 115 mm, at least 120 mm, at least 125 mm, at least 130 mm, at least 135 mm, at least 140 mm, at least 145 mm or at least 150 mm. In another embodiment, the micro-organ may have a length of 5-100 mm, 10-100 mm, 15-100 mm, 20-100 mm, 25-10 mm, 30-100 mm, 35-100 mm, 40-100 mm, 45-100 mm, 50-100 mm, 55-100 mm, 60-100 mm, 65-100 mm, 70-100 mm, 75-100 mm, 80-100 mm, 85-100 mm, 90-100 mm, 5-90 mm, 10-90 mm, 15-90 mm, 20-90 mm, 25-10 mm, 30-90 mm, 35-90 mm, 40-90 mm, 45-90 mm, 50-90 mm, 55-90 mm, 60-90 mm, 65-90 mm, 70-90 mm, 75-90 mm, 80-90 mm, 5-80 mm, 10-80 mm, 15-80 mm, 20-80 mm, 25-10 mm, 30-80 mm, 35-80 mm, 40-80 mm, 45-80 mm, 50-80 mm, 55-80 mm, 60-80 mm, 65-80 mm, 70-80 mm, 5-70 mm, 10-70 mm, 15-70 mm, 20-70 mm, 25-10 mm, 30-70 mm, 35-70 mm, 40-70 mm, 45-70 mm, 50-70 mm, 55-70 mm, 60-70 mm, 5-60 mm, 10-60 mm, 15-60 mm, 20-60 mm, 25-10 mm, 30-60 mm, 35-60 mm, 40-60 mm, 45-60 mm, 50-60 mm, 5-50 mm, 10-50 mm, 15-50 mm, 20-50 mm, 25-10 mm, 30-50 mm, 35-50 mm, 40-50 mm, 5-40 mm, 10-40 mm, 15-40 mm, 20-40 mm, 25-10 mm, 30-40 mm, 5-30 mm, 10-30 mm, 15-30 mm, 20-30 mm, 5-20 mm, 10-20 mm or 5-10 mm.

Hyaluronidase

The intramuscular or subcutaneous localized injection of NAVs of the invention can include hyaluronidase, which catalyzes the hydrolysis of hyaluronan. By catalyzing the hydrolysis of hyaluronan, a constituent of the interstitial barrier, hyaluronidase lowers the viscosity of hyaluronan, thereby increasing tissue permeability (Frost, Expert Opin. Drug Deliv. (2007) 4:427-440; herein incorporated by reference in its entirety). It is useful to speed their dispersion and systemic distribution of encoded proteins produced by transfected cells. Alternatively, the hyaluronidase can be used to increase the number of cells exposed to a polynucleotide of the invention administered intramuscularly or subcutaneously.

Nanoparticle Mimics

The NAVs of the invention may be encapsulated within and/or absorbed to a nanoparticle mimic. A nanoparticle mimic can mimic the delivery function organisms or particles such as, but not limited to, pathogens, viruses, bacteria, fungus, parasites, prions and cells. As a non-limiting example the NAVs of the invention may be encapsulated in a non-viron particle which can mimic the delivery function of a virus (see International Pub. No. WO2012006376 and US Patent Publication No. US20130171241 and US20130195968, the contents of each of which are herein incorporated by reference in its entirety).

Nanotubes

The NAVs of the invention can be attached or otherwise bound to at least one nanotube such as, but not limited to, rosette nanotubes, rosette nanotubes having twin bases with a linker, carbon nanotubes and/or single-walled carbon nanotubes,

The NAVs may be bound to the nanotubes through forces such as, but not limited to, steric, ionic, covalent and/or other forces.

In one embodiment, the nanotube can release one or more NAVs into cells. The size and/or the surface structure of at least one nanotube may be altered so as to govern the interaction of the nanotubes within the body and/or to attach or bind to the NAVs disclosed herein. In one embodiment, the building block and/or the functional groups attached to the building block of the at least one nanotube may be altered to adjust the dimensions and/or properties of the nanotube. As a non-limiting example, the length of the nanotubes may be altered to hinder the nanotubes from passing through the holes in the walls of normal blood vessels but still small enough to pass through the larger holes in the blood vessels of tumor tissue.

In one embodiment, at least one nanotube may also be coated with delivery enhancing compounds including polymers, such as, but not limited to, polyethylene glycol. In another embodiment, at least one nanotube and/or the NAVs may be mixed with pharmaceutically acceptable excipients and/or delivery vehicles.

In one embodiment, the NAVs are attached and/or otherwise bound to at least one rosette nanotube. The rosette nanotubes may be formed by a process known in the art and/or by the process described in International Publication No. WO2012094304, herein incorporated by reference in its entirety. At least one NAV may be attached and/or otherwise bound to at least one rosette nanotube by a process as described in International Publication No. WO2012094304, herein incorporated by reference in its entirety, where rosette nanotubes or modules forming rosette nanotubes are mixed in aqueous media with at least one NAV under conditions which may cause at least one RNAVs to attach or otherwise bind to the rosette nanotubes.

In one embodiment, the NAVs may be attached to and/or otherwise bound to at least one carbon nanotube. As a non-limiting example, the NAVs may be bound to a linking agent and the linked agent may be bound to the carbon nanotube (See e.g., U.S. Pat. No. 8,246,995; herein incorporated by reference in its entirety). The carbon nanotube may be a single-walled nanotube (See e.g., U.S. Pat. No. 8,246,995; herein incorporated by reference in its entirety).

Conjugates

The NAVs of the invention include conjugates, such as a polynucleotide covalently linked to a carrier or targeting group, or including two encoding regions that together produce a fusion protein (e.g., bearing a targeting group and therapeutic protein or peptide).

The conjugates of the invention include a naturally occurring substance, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), high-density lipoprotein (HDL), or globulin); an carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid); or a lipid. The ligand may also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid, an oligonucleotide (e.g. an aptamer). Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L-lactide-co-glycolied) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, quaternary salt of a polyamine, or an alpha helical peptide.

Representative U.S. patents that teach the preparation of polynucleotide conjugates, particularly to RNA, include, but are not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and U.S. Pat. Nos. 5,688,941; 6,294,664; 6,320,017; 6,576,752; 6,783,931; 6,900,297; 7,037,646; each of which is herein incorporated by reference in their entireties.

In one embodiment, the conjugate of the present invention may function as a carrier for the NAVs of the present invention. The conjugate may comprise a cationic polymer such as, but not limited to, polyamine, polylysine, polyalkylenimine, and polyethylenimine which may be grafted to with poly(ethylene glycol). As a non-limiting example, the conjugate may be similar to the polymeric conjugate and the method of synthesizing the polymeric conjugate described in U.S. Pat. No. 6,586,524 herein incorporated by reference in its entirety.

A non-limiting example of a method for conjugation to a substrate is described in US Patent Publication No. US20130211249, the contents of which are herein incorporated by reference in its entirety. The method may be used to make a conjugated polymeric particle comprising a NAV.

The conjugates can also include targeting groups, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a kidney cell. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, an RGD peptide, an RGD peptide mimetic or an aptamer.

Targeting groups can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a cancer cell, endothelial cell, or bone cell. Targeting groups may also include hormones and hormone receptors. They can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, or aptamers. The ligand can be, for example, a lipopolysaccharide, or an activator of p38 MAP kinase.

The targeting group can be any ligand that is capable of targeting a specific receptor. Examples include, without limitation, folate, GalNAc, galactose, mannose, mannose-6P, apatamers, integrin receptor ligands, chemokine receptor ligands, transferrin, biotin, serotonin receptor ligands, PSMA, endothelin, GCPII, somatostatin, LDL, and HDL ligands. In particular embodiments, the targeting group is an aptamer. The aptamer can be unmodified or have any combination of modifications disclosed herein.

As a non-limiting example, the targeting group may be a glutathione receptor (GR)-binding conjugate for targeted delivery across the blood-central nervious system barrier (See e.g., US Patent Publication No. US2013021661012, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the conjugate of the present invention may be a synergistic biomolecule-polymer conjugate. The synergistic biomolecule-polymer conjugate may be long-acting continuous-release system to provide a greater therapeutic efficacy. The synergistic biomolecule-polymer conjugate may be those described in US Patent Publication No. US20130195799, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the conjugate which may be used in the present invention may be an aptamer conjugate. Non-limiting examples of apatamer conjugates are described in International Patent Publication No. WO2012040524, the contents of which are herein incorporated by reference in its entirety. The aptamer conjugates may be used to provide targerted delivery of formulations comprising NAVs.

In one embodiment, the conjugate which may be used in the present invention may be an amine containing polymer conjugate. Non-limiting examples of amine containing polymer conjugate are described in U.S. Pat. No. 8,507,653, the contents of which are herein incorporated by reference in its entirety. The factor IX moiety polymer conjugate may be ucomprise releasable linkages to release the NAVs upon and/or after delivery to a subject.

In one embodiment, pharmaceutical compositions of the present invention may include chemical modifications such as, but not limited to, modifications similar to locked nucleic acids.

Representative U.S. Patents that teach the preparation of locked nucleic acid (LNA) such as those from Santaris, include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,670,461; 6,794,499; 6,998,484; 7,053,207; 7,084,125; and U.S. Pat. No. 7,399,845, each of which is herein incorporated by reference in its entirety.

Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found, for example, in Nielsen et al., Science, 1991, 254, 1497-1500.

Some embodiments featured in the invention include polynucleotides with phosphorothioate backbones and oligonucleosides with other modified backbones, and in particular —CH₂—NH—CH₂—, —CH₂—N(CH₃)—O—CH₂-[known as a methylene (methylimino) or MMI backbone], —CH₂—O—N(CH₃)—CH₂—, —CH₂—N(CH₃)—N(CH₃)—CH₂— and —N(CH₃)—CH₂—CH₂-[wherein the native phosphodiester backbone is represented as —O—P(O)₂—O—CH₂-] of the above-referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above-referenced U.S. Pat. No. 5,602,240. In some embodiments, the polynucletotides featured herein have morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.

Modifications at the 2′ position may also aid in delivery. Preferably, modifications at the 2′ position are not located in a polypeptide-coding sequence, i.e., not in a translatable region. Modifications at the 2′ position may be located in a 5′UTR, a 3′UTR and/or a tailing region. Modifications at the 2′ position can include one of the following at the 2′ position: H (i.e., 2′-deoxy); F; O—, S—, or N-alkyl; O—, S—, or N-alkenyl; O—, S— or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl and alkynyl. Exemplary suitable modifications include O[(CH₂)_(n)O]_(m)CH₃, O(CH₂)._(n)OCH₃, O(CH₂)_(n)NH₂, O(CH₂)_(n)CH₃, O(CH₂)_(n)ONH₂, and O(CH₂)_(n)ON[(CH₂)_(n)CH₃)]₂, where n and m are from 1 to about 10. In other embodiments, the polynucleotides include one of the following at the 2′ position: C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties, or a group for improving the pharmacodynamic properties, and other substituents having similar properties. In some embodiments, the modification includes a 2′-methoxyethoxy (2′-O—CH₂CH₂OCH₃, also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al., Helv. Chin. Acta, 1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2′-dimethylaminooxyethoxy, i.e., a O(CH₂)₂ON(CH₃)₂ group, also known as 2′-DMAOE, as described in examples herein below, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethylaminoethoxyethyl or 2′-DMAEOE), i.e., 2′-O—CH₂—O—CH₂—N(CH₂)₂, also described in examples herein below. Other modifications include 2′-methoxy (2′-OCH₃), 2′-aminopropoxy (2′-OCH₂CH₂CH₂NH₂) and 2′-fluoro (2′-F). Similar modifications may also be made at other positions, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked dsRNAs and the 5′ position of 5′ terminal nucleotide. Polynucleotides of the invention may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920; the contents of each of which is herein incorporated by reference in their entirety.

In one embodiment, the NAVs may be conjugated to an agent to enhance delivery. As a non-limiting example, the agent may be a monomer or polymer such as a targeting monomer or a polymer having targeting blocks as described in International Publication No. WO2011062965, herein incorporated by reference in its entirety. In another non-limiting example, the agent may be a transport agent covalently coupled to the polynucleotides of the present invention (See e.g., U.S. Pat. Nos. 6,835,393 and 7,374,778, each of which is herein incorporated by reference in its entirety). In yet another non-limiting example, the agent may be a membrane barrier transport enhancing agent such as those described in U.S. Pat. Nos. 7,737,108 and 8,003,129, each of which is herein incorporated by reference in its entirety.

In another embodiment, polynucleotides may be conjugated to SMARTT POLYMER TECHNOLOGY® (PHASERX®, Inc. Seattle, Wash.).

In another aspect, the conjugate may be a peptide that selectively directs the nanoparticle to neurons in a tissue or organism. As a non-limiting example, the peptide used may be, but is not limited to, the peptides described in US Patent Publication No US20130129627, herein incorporated by reference in its entirety.

In yet another aspect, the conjugate may be a peptide that can assist in crossing the blood-brain barrier.

Self-Assembled Nanoparticles

Nucleic Acid Self-Assembled Nanoparticles

Self-assembled nanoparticles have a well-defined size which may be precisely controlled as the nucleic acid strands may be easily reprogrammable. For example, the optimal particle size for a cancer-targeting nanodelivery carrier is 20-100 nm as a diameter greater than 20 nm avoids renal clearance and enhances delivery to certain tumors through enhanced permeability and retention effect. (Lee et al., Nature Nanotechnology 2012 7:389-393; herein incorporated by reference in its entirety). Such self-assembling nanoparticles may be useful in formulating the NAVs of the invention.

In one embodiment, the NAVs disclosed herein may be formulated as self-assembled nanoparticles. As a non-limiting example, nucleic acids may be used to make nanoparticles which may be used in a delivery system for the NAVs of the present invention (See e.g., International Pub. No. WO2012125987; herein incorporated by reference in its entirety).

In one embodiment, the nucleic acid self-assembled nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.

The metallic nanoparticle which may be used in the present invention may be a pH-sensitive nanoparticle such as, but not limited to, those described in US Patent Publication No US20130138032, herein incorporated by reference in its entirety.

In one aspect, the metallic and/or metal-allow nanoparticles may be made by the methods described in US Patent Publication No US20130133483, herein incorporated by reference in its entirety

Polymer-Based Self-Assembled Nanoparticles

Polymers may be used to form sheets which self-assembled into nanoparticles. These nanoparticles may be used to deliver the NAVs of the present invention. In one embodiment, these self-assembled nanoparticles may be microsponges formed of long polymers of RNA hairpins which form into crystalline ‘pleated’ sheets before self-assembling into microsponges. These microsponges are densely-packed sponge like microparticles which may function as an efficient carrier and may be able to deliver cargo to a cell. The microsponges may be from lum to 300 nm in diameter. The microsponges may be complexed with other agents known in the art to form larger microsponges. As a non-limiting example, the microsponge may be complexed with an agent to form an outer layer to promote cellular uptake such as polycation polyethyleneime (PEI). This complex can form a 250-nm diameter particle that can remain stable at high temperatures (150° C.) (Grabow and Jaegar, Nature Materials 2012, 11:269-269; herein incorporated by reference in its entirety). Additionally these micro sponges may be able to exhibit an extraordinary degree of protection from degradation by ribonucleases.

In another embodiment, the polymer-based self-assembled nanoparticles such as, but not limited to, microsponges, may be fully programmable nanoparticles. The geometry, size and stoichiometry of the nanoparticle may be precisely controlled to create the optimal nanoparticle for delivery of cargo such as, but not limited to, NAVs.

In yet another embodiment, the polymer based nanoparticle may comprise a non-nucleic acid polymer comprising a plurality of heterogenous monomers such as those described in Interantional Publication No. WO2013009736, the contents of which are herein incorporated by reference in its entirety.

Self-Assembled Macromolecules

The NAVs may be formulated in amphiphilic macromolecules (AMs) for delivery. AMs comprise biocompatible amphiphilic polymers which have an alkylated sugar backbone covalently linked to poly(ethylene glycol). In aqueous solution, the AMs self-assemble to form micelles. Non-limiting examples of methods of forming AMs and AMs are described in US Patent Publication No. US20130217753, the contents of which are herein incorporated by reference in its entirety.

Inorganic Nanoparticles

The NAVs of the present invention may be formulated in inorganic nanoparticles (U.S. Pat. No. 8,257,745, herein incorporated by reference in its entirety). The inorganic nanoparticles may include, but are not limited to, clay substances that are water swellable. As a non-limiting example, the inorganic nanoparticle may include synthetic smectite clays which are made from simple silicates (See e.g., U.S. Pat. Nos. 5,585,108 and 8,257,745 each of which are herein incorporated by reference in their entirety).

In one embodiment, the inorganic nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.

Semi-Conductive and Metallic Nanoparticles

The NAVs of the present invention may be formulated in water-dispersible nanoparticle comprising a semiconductive or metallic material (U.S. Pub. No. 20120228565; herein incorporated by reference in its entirety) or formed in a magnetic nanoparticle (U.S. Pub. No. 20120265001 and 20120283503; each of which is herein incorporated by reference in its entirety). The water-dispersible nanoparticles may be hydrophobic nanoparticles or hydrophilic nanoparticles.

In one embodiment, the semi-conductive and/or metallic nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.

Surgical Sealants: Gels and Hydrogels

In one embodiment, the NAVs disclosed herein may be encapsulated into any hydrogel known in the art which may form a gel when injected into a subject. Hydrogels are a network of polymer chains that are hydrophilic, and are sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are highly absorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. The hydrogel described herein may used to encapsulate lipid nanoparticles which are biocompatible, biodegradable and/or porous. A hydrogel can be made in situ from solution injection or implanted.

As a non-limiting example, the hydrogel may be an aptamer-functionalized hydrogel. The aptamer-functionalized hydrogel may be programmed to release one or more polynucleotides using nucleic acid hybridization. (Battig et al., J. Am. Chem. Society. 2012 134:12410-12413; the contents of which is herein incorporated by reference in its entirety).

As another non-limiting example, the hydrogel may be a shaped as an inverted opal. The opal hydrogels exhibit higher swelling ratios and the swelling kinetics is an order of magnitude faster than conventional hydrogels as well. Methods of producing opal hydrogels and description of opal hydrogels are described in International Pub. No. WO2012148684, the contents of which is herein incorporated by reference in its entirety.

In yet another non-limiting example, the hydrogel may be an antibacterial hydrogel. The antibacterial hydrogel may comprise a pharmaceutical acceptable salt or organic material such as, but not limited to pharmaceutical grade and/or medical grade silver salt and aloe vera gel or extract. (International Pub. No. WO2012151438, the contents of which are herein incorporated by reference in its entirety).

In one embodiment, a NAV may be encapsulated in a lipid nanoparticle and then the lipid nanoparticle may be encapsulated into a hydrogel.

In one embodiment, the NAVs disclosed herein may be encapsulated into any gel known in the art. As a non-limiting example the gel may be a fluorouracil injectable gel or a fluorouracil injectable gel containing a chemical compound and/or drug known in the art. As another example, the NAVs may be encapsulated in a fluorouracil gel containing epinephrine (See e.g., Smith et al. Cancer Chemotherapty and Pharmacology, 1999 44(4):267-274; the contents of which are herein incorporated by reference in its entirety).

In one embodiment, the NAVs disclosed herein may be encapsulated into a fibrin gel, fibrin hydrogel or fibrin glue.

In another embodiment, the NAVs may be formulated in a lipid nanoparticle or a rapidly eliminated lipid nanoparticle prior to being encapsulated into a fibrin gel, fibrin hydrogel or a fibrin glue. In yet another embodiment, the NAVs may be formulated as a lipoplex prior to being encapsulated into a fibrin gel, hydrogel or a fibrin glue. Fibrin gels, hydrogels and glues comprise two components, a fibrinogen solution and a thrombin solution which is rich in calcium (See e.g., Spicer and Mikos, Journal of Controlled Release 2010. 148: 49-55; Kidd et al. Journal of Controlled Release 2012. 157:80-85; each of which is herein incorporated by reference in its entirety). The concentration of the components of the fibrin gel, hydrogel and/or glue can be altered to change the characteristics, the network mesh size, and/or the degradation characteristics of the gel, hydrogel and/or glue such as, but not limited to changing the release characteristics of the fibrin gel, hydrogel and/or glue. (See e.g., Spicer and Mikos, Journal of Controlled Release 2010. 148: 49-55; Kidd et al. Journal of Controlled Release 2012. 157:80-85; Catelas et al. Tissue Engineering 2008. 14:119-128; each of which is herein incorporated by reference in its entirety). This feature may be advantageous when used to deliver the modified mRNA disclosed herein. (See e.g., Kidd et al. Journal of Controlled Release 2012. 157:80-85; Catelas et al. Tissue Engineering 2008. 14:119-128; each of which is herein incorporated by reference in its entirety).

In one embodiment, the NAVs disclosed herein may be used with hydrogels such as, but not limited to, the hydrogels described in U.S. Patent Application No. 20130071450 or 20130211249, the contents of each of which is herein incorporated by reference in its entirety.

As a non-limiting example, the hydrogels which may be used in the present invention may be made by the methods described in International Patent Publication No. WO2013124620, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the NAVs disclosed herein may be formulated for transdermal delivery. The formulation may comprise at least one hydrogel described in U.S. Patent Application No. 20130071450, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the hydrogel which may be used in the present invention is described in U.S. Pat. Nos. 8,420,605, 8,415,325 and/or International Patent Publication No. WO2013091001 and WO2013124620, the contents of each of which are herein incorporated by reference in its entirety.

In one embodiment, the hydrogel which may be used in the present invention may be, but is not limited to, ATRIGEL® (QLT Inc. Vancouver, British Columbia), chitosan, aliginate, collagen or hyaluronic acid hydrogel.

In another embodiment, the hydrogel which may be used in the present invention is a crosslinked methacrylate. As a non-limiting example, the hydrogel of the present invention may be used in wound dressings.

The hydrogel which may be used in the present invention may also be complexed with agents and excipients described herein including, but not limited to PEI, PVA, poly-lysine, Poloxamer 124, Poloxamer 181, Poloxamer 182, Poloxamer 407, Poloxamer 237, Poloxamer 331 and Poloxamer 338. Complexing the hydrogel with agents and/or excipients may help improve mRNA stability and uptake in a cell, tissue and/or organism. As a non-limiting example, a hydrogel may be complexed with Poloxamer 188 to improve the stability and uptake of mRNA.

In one embodiment, the NAVs disclosed herein may be formulated in a surgical sealant. The surgical sealant may be, but is not limited to, fibrinogen polymer based sealants (Ethicon Inc. Cornelia, Ga.), TISSELL® (Baxter International, Inc Deerfield, Ill.) or PEG-based sealants such as, but not limited to, COSEAL® (Baxter International, Inc Deerfield, Ill.) and DURASEAL™ (trilysine amine/PEG-ester) (Covidien, Waltham, Mass.).

In one embodiment, NAVs may be formulated in COSEAL® or co-administered with or administered after a cell, tissue or organism is administered COSEAL®. COSEAL® comprises two synthetic polyethylene glycols (PEGs) (pentaerythritol PEG ester tetra-succinimidyl and pentaerythritol PEG ether tetra-thiol), a dilute hydrogen chloride solution, and a sodium phosphate/sodium carbonate solution. The PEGs are kept separate from the sodium phosphate/sodium carbonate solution in the dilute hydrogen chloride solution until administration. After administration a hydrogel is formed, which may adhere to tissue, and forms a stiff gel in seconds which is resorbed within 30 days.

In another embodiment, the NAVs disclosed herein may be formulated in a hydrogel comprising a macromolecular matrix. The macromolecular matrix may comprise a hyaluronic acid component which may be crosslinked to a collagent component. The hydrogel used in the present invention may be, but is not limited to, the hydrogels described in International Patent Publication No. WO2013106715, the contents of which are herein incorporated by reference in its entirety.

In yet another embodiment, the NAVs disclosed herein may be formulated in a chitosan glycerophosphate (CGP) hydrogel. The formulation may further comprise a chitosanase in an effect amount to dissolve the CGP hydrogel and release the NAVs associated with the CGP hydrogel. As a non-limiting example, the NAVs may be formulated in the controlled release delivery system comprising a CGP hydrogel described in US Patent Publication No. US20130189241, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs disclosed herein may be formulated in a hydrogel formulated for controlled release such as, but not limited to, the porous matrix composites and formulations described in US Patent Publication No. US20130196915, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the NAVs disclosed herein may be formulated in a hydrogel comprising heterobifunctional poly(alkylene oxides) which may have degradable linkages. Non-limiting examples of heterobifunctional poly(alkylene oxides) are described in U.S. Pat. No. 8,497,357, the contents of which are herein incorporated by reference in its entirety.

In yet another embodiment, the NAVs may be formulated in a hydrogel which may be used as an insulin delivery system. As a non-limiting example, the hydrogel may be a glucose binding amphiphilic peptide hydrogel as described in International Patent Publication No. WO2013123491, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the hydrogel may be a microgel such as the glucose-responsive microgels described in International Patent Publication No. WO2013123492, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs may be formulated in a hydrogel system such as, but not limited to, a multi-compartment hydrogel. A non-limiting example of a multi-compartment hydrogel and methods of making the hydrogel is described in International Patent Publication No. WO2013124855, the contents of which are herein incorporated by reference in its entirety. The multi-compartment hydrogel may be used to repair or regenerate damaged tissue in a subject.

In another embodiment, the NAVs may be formulated in a cucurbituril-based hydrogel. A non-limiting example of a cucurbituril-based hydrogel is described in international Patent Publication No. WO2013124654, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the NAVs disclosed herein may be formulated in a PEG-based surgical sealant or hydrogel.

In one embodiment, the surgical sealant or hydrogel may include at least one, at least two, at least three, at least four, at least five, at least six or more than six

PEG lipids. The PEG lipids may be selected from, but are not limited to, pentaerythritol PEG ester tetra-succinimidyl and pentaerythritol PEG ether tetra-thiol, PEG-c-DOMG, PEG-DMG (1,2-Dimyristoyl-sn-glycerol, methoxypolyethylene Glycol), PEG-DS G (1,2-Distearoyl-sn-glycerol, methoxypolyethylene Glycol), PEG-DPG (1,2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol), PEG-DSA (PEG coupled to 1,2-distearyloxypropyl-3-amine), PEG-DMA (PEG coupled to 1,2-dimyristyloxypropyl-3-amine, PEG-c-DNA, PEG-c-DMA, PEG-S-DSG, PEG-c-DMA, PEG-DPG, PEG-DMG 2000 and those described herein and/or known in the art. The concentration and/or ratio of the PEG lipids in the surgical sealant or hydrogel may be varied in order to optimize the formulation for delivery and/or administration.

The amount of buffer and/or acid used in combination with the PEG lipids of the surgical sealant or hydrogel may also be varied. In one non-limiting example, the ratio of buffer and/or acid with PEG lipids is 1:1. As a non-limiting example, the amount of buffer and/or acid used with the PEG lipids may be increased to alter the ratio of buffer/acid to PEG in order to optimize the surgical sealant or hydrogel. As another non-limiting example, the amount of buffer and/or acid used with the PEG lipids may be decreased to alter the ratio of buffer/acid to PEG in order to optimize the surgical sealant or hydrogel.

The amount of NAVs loaded into the buffer, acid and/or PEG lipid may be varied. The amount of NAVs loaded into the buffer, acid and/or PEG lipid may be, but is not limited to, at least 1 uL, at least 2 uL, at least 5 uL, at least 10 uL, at least 15 uL, at least 20 uL, at least 25 uL, at least 30 uL, at least 35 uL, at least 40 uL, at least 45 ul, at least 50 uL, at least 55 uL, at least 60 uL, at least 65 uL, at least 70 uL, at least 75 uL, at least 80 uL, at least 85 uL, at least 90 uL, at least 100 uL, at least 125 uL, at least 150 uL, at least 200 uL, at least 250 uL, at least 300 uL, at least 350 uL, at least 400 uL, at least 450 uL, at least 500 uL or more than 500 uL.

In one embodiment, the NAVs of the present invention may be loaded in PEGs and also in the buffer or the acid. The amount of NAVs loaded in the PEG may be the same, greater or less than the amount loaded in the buffer or acid. In another embodiment, the NAVs may be formulated, by the methods described herein and/or known in the art, prior to loading in the PEGs, buffer or acid.

A non-limiting example of a PEG-based hydrogel which may be used in the present invention is described in U.S. Pat. No. 8,524,215, the contents of which is herein incorporated by reference in its entirety. The PEG-based hyrdrogel may be an absorbable hydrogel prepared from a multi-arm PEG-vinylsulfone having about 3 to about 8 arms and a multi-arm-PEG-R-sulfhydryl having about 3 to about 8 arms (See e.g., U.S. Pat. No. 8,524,215). In one embodiment, the PEG-based hydrogel may be an absorbable hydrogel. While not wishing to be bound by theory, an absorbable PEG-based hydrogel may be beneficial to reduce the permanent chronic foreign body reaction since the absorbable hydrogel can be absorbed and passed by the body.

In one embodiment, the hydrogel may be a thermosensitive hydrogel. In one aspect the thermosensitive hydrogel may be, but is not limited to, a triblock polymer such as those described herein and known in the art. As a non-limiting example, the tri-block polymer may be PEG-PLGA-PEG (see e.g., the thermosensitive hydrogel (PEG-PLGA-PEG) was used as a TGF-beta1 gene delivery vehicle in Lee et al. Thermosensitive Hydrogel as a Tgf-β1 Gene Delivery Vehicle Enhances Diabetic Wound Healing. Pharmaceutical Research, 2003 20(12): 1995-2000; as a controlled gene delivery system in Li et al. Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel. Pharmaceutical Research 2003 20(6):884-888; and Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253; each of which is herein incorporated by reference in its entirety). As a non-limiting example, the thermosensitive hydrogel may be used to make nanoparticles and liposomes by the methods described in International Publication No. WO2013123407, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the hydrogel may be a biodegradable copolymer hydrogel (see e.g., the biodegradable hydrogels described by Nguyen and Lee (Injectable Biodegradable Hydrogels. Macromolecular Bioscience. 2010 10:563-579), herein incorporated by reference in its entirety). These hydrogels may exhibit a sol-gel phase transition that respond to external stimuli such as, but not limited to, temperature changes, pH alternations or both. Non-limiting examples of biodegradable copolymer hydrogels include triblock copolymers PEG-PLLA-PEG, PEG-PLA-PEG (see e.g., Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253, herein incorporated by reference in its entirety), PLGA-PEG-PLGA, PEG-PCL-PEG, PCL-PEG-PCL, polyesters such as poly[(R)-3-hydroxybutyrate] (PHB), polyphosphazenes such as L-sioleucine ethyl ester (IleOEt), D,L-leucine ethyl ester (LeuOEt), L-valine ethyl ester (ValOEt), or di-, tri- and oligo-peptides, polypeptides and chitosan. Temperature and pH sensitive polymers which may be used to form the biodegradable copolymer hydrogels include, but are not limited to, sulfamethazine-, poly(β-amino ester)-, poly(amino urethane)-, and poly(amidoamine)-based polymers. Formulations of the biodegradable copolymer hydrogels and NAVs may be administered using site-specific control of release behavior.

In one embodiment, the hydrogel used in the present invention may be a PEG based hydrogel such as, but not limited to, those described in International Patent Publication No WO2013082590, herein incorporated by reference in its entirety. The PEG based hydrogel may have, but is not limited to, an overall polymer weight concentration of less than or equal to 50% at the time of curing. As a non-limiting example, the PEG based hydrogel may be made by the methods described in International Patent Publication No WO2013082590, the contents of which are herein incorporated by reference in its entirety.

In another embodiment, the NAVs may be formulated in a nanostructured gel composition. The nanostructured gel may be capable of controlled release of the encapsulated NAVs. Non-limiting examples of nanostructed gels or self-assembled gels are described in International Patent Publication No. WO2012040623, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the concentration of the NAVs of the present invention in the surgical sealants, gels and/or hydrogels may be selected to provide a dosage within the range to have the desired therapeutic effect.

In one embodiment, the concentration of the polynucleotides of the NAV of the present invention in the surgical sealants, gels and/or hydrogels may be at least 0.001 mg to at least 150 mg in at least 0.1 ml to at least 30 ml of the surgical sealant, gel or hydrogel. The concentration of the polynucleotides of the present invention may be at least 0.001 mg, at least 0.005 mg, at least 0.01 mg, at least 0.05 mg, at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 5 mg, at least 7 mg, at least 10 mg, at least 12, at least 15 mg, at least 17 mg, at least 20 mg, at least 22 mg, at least 25 mg, at least 27 mg, at least 30 mg, at least 32 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg or at least 150 mg in at least 0.1 ml, at least 0.2 ml, at least 0.3 ml, at least 0.4 ml, at least 0.5 ml, at least 0.6 ml, at least 0.7 ml, at least 0.8 ml, at least 0.9 ml, at least 1 ml, at least 2 ml, at least 3 ml, at least 4 ml, at least 5 ml, at least 6 ml, at least 7 ml, at least 8 ml, at least 9 ml, at least 10 ml, at least 11 ml, at least 12 ml, at least 13 ml, at least 14 ml, at least 15 ml, at least 16 ml, at least 17 ml, at least 18 ml, at least 19 ml, at least 20 ml, at least 21 ml, at least 22 ml, at least 23 ml, at least 24 ml, at least 25 ml, at least 26 ml, at least 27 ml, at least 28 ml, at least 29 ml or at least 30 ml of the surgical sealant, gel or hydrogel.

In another embodiment, concentration of the polynucleotides of the NAV of the present invention in the surgical sealants, gels and/or hydrogels may be at least 0.001 mg/ml at least 0.005 mg/ml, at least 0.01 mg/ml, at least 0.05 mg/ml, at least 0.1 mg/ml, at least 0.5 mg/ml, at least 1 mg/ml, at least 5 mg/ml, at least 7 mg/ml, at least 10 mg/ml, at least 12, at least 15 mg/ml, at least 17 mg/ml, at least 20 mg/ml, at least 22 mg/ml, at least 25 mg/ml, at least 27 mg/ml, at least 30 mg/ml, at least 32 mg/ml, at least 35 mg/ml, at least 40 mg/ml, at least 45 mg/ml or at least 50 mg/ml.

Technology allowing for large subcutaneous infusion volumes which are known in the art, such as, but not limited to, HYLENEX® (Halozyme Therapeutics, San Diego, Calif.) may also be used. The dispersion and/or adsorption of the modified mRNA described herein may be increased with the use of HYLENEX® as HYLENEX® temporarily breaks down hyaluronic acid causing a temporty degradation in the subcutaneous space (for about 24 hours) just beneath the outside surface of the skin opening microscopic channels and allowing fluid or drugs to be dispersed and absorbed in the body.

Suspension Formulations

In some embodiments, suspension formulations are provided comprising NAVs, water immiscible oil depots, surfactants and/or co-surfactants and/or co-solvents. Combinations of oils and surfactants may enable suspension formulation with NAVs. Delivery of NAVs in a water immiscible depot may be used to improve bioavailability through sustained release of NAVs from the depot to the surrounding physiologic environment and prevent polynucleotides degradation by nucleases.

In some embodiments, suspension formulations of NAV may be prepared using combinations of polynucleotides, oil-based solutions and surfactants. Such formulations may be prepared as a two-part system comprising an aqueous phase comprising polynucleotides and an oil-based phase comprising oil and surfactants. Exemplary oils for suspension formulations may include, but are not limited to sesame oil and Miglyol (comprising esters of saturated coconut and palmkernel oil-derived caprylic and capric fatty acids and glycerin or propylene glycol), corn oil, soybean oil, peanut oil, beeswax and/or palm seed oil. Exemplary surfactants may include, but are not limited to Cremophor, polysorbate 20, polysorbate 80, polyethylene glycol, transcutol, Capmul®, labrasol, isopropyl myristate, and/or Span 80. In some embodiments, suspensions may comprise co-solvents including, but not limited to ethanol, glycerol and/or propylene glycol.

Suspensions may be formed by first preparing NAV formulation comprising an aqueous solution of polynucleotide and an oil-based phase comprising one or more surfactants. Suspension formation occurs as a result of mixing the two phases (aqueous and oil-based). In some embodiments, such a suspension may be delivered to an aqueous phase to form an oil-in-water emulsion. In some embodiments, delivery of a suspension to an aqueous phase results in the formation of an oil-in-water emulsion in which the oil-based phase comprising polynucleotides forms droplets that may range in size from nanometer-sized droplets to micrometer-sized droplets.

In some embodiments, specific combinations of oils, surfactants, cosurfactants and/or co-solvents may be utilized to suspend NAVs in the oil phase and/or to form oil-in-water emulsions upon delivery into an aqueous environment.

In some embodiments, suspensions may provide modulation of the release of NAVs into the surrounding environment. In such embodiments, NAV release may be modulated by diffusion from a water immiscible depot followed by resolubilization into a surrounding environment (e.g. an aqueous environment).

In some embodiments, NAVs within a water immiscible depot (e.g. suspended within an oil phase) may result in altered polynucleotides stability (e.g. altered degradation by nucleases).

In some embodiments, NAVs may be formulated such that upon injection, an emulsion forms spontaneously (e.g. when delivered to an aqueous phase). Such particle formation may provide a high surface area to volume ratio for release of polynucleotides from an oil phase to an aqueous phase.

In one embodiment, the NAVs may be formulated in a nanoemulsion such as, but not limited to, the nanoemulsions described in U.S. Pat. No. 8,496,945, the contents of which are herein incorporated by reference in its entirety. The nanoemulsions may comprise nanoparticles described herein. As a non-limiting example, the nanoparticles may comprise a liquid hydrophobic core which may be surrounded or coated with a lipid or surfactant layer. The lipid or surfactant layer may comprise at least one membrane-integrating peptide and may also comprise a targeting ligand (see e.g., U.S. Pat. No. 8,496,945, the contents of which are herein incorporated by reference in its entirety).

Cations and Anions

Formulations of NAVs disclosed herein may include cations or anions. In one embodiment, the formulations include metal cations such as, but not limited to, Zn2+, Ca2+, Cu2+, Mg+ and combinations thereof. As a non-limiting example, formulations may include polymers and a RNAV complexed with a metal cation (See e.g., U.S. Pat. Nos. 6,265,389 and 6,555,525, each of which is herein incorporated by reference in its entirety).

In some embodiments, cationic nanoparticles comprising combinations of divalent and monovalent cations may be formulated with NAVs. Such nanoparticles may form spontaneously in solution over a give period (e.g. hours, days, etc). Such nanoparticles do not form in the presence of divalent cations alone or in the presence of monovalent cations alone. The delivery of NAVs in cationic nanoparticles or in one or more depot comprising cationic nanoparticles may improve NAV bioavailability by acting as a long-acting depot and/or reducing the rate of degradation by nucleases.

Molded Nanoparticles and Microparticles

The NAVs disclosed herein may be formulated in nanoparticles and/or microparticles. These nanoparticles and/or microparticles may be molded into any size shape and chemistry. As an example, the nanoparticles and/or microparticles may be made using the PRINT® technology by LIQUIDA TECHNOLOGIES® (Morrisville, N.C.) (See e.g., International Pub. No. WO2007024323; the contents of which are herein incorporated by reference in its entirety).

In one embodiment, the molded nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.

In one embodiment, the NAVs of the present invention may be formulated in microparticles. The microparticles may contain a core of the NAVs and a cortext of a biocompatible and/or biodegradable polymer. As a non-limiting example, the microparticles which may be used with the present invention may be those described in U.S. Pat. No. 8,460,709, U.S. Patent Publication No. US20130129830 and International Patent Publication No WO2013075068, each of which is herein incorporated by reference in its entirety. As another non-limiting example, the microparticles may be designed to extend the release of the NAVs of the present invention over a desired period of time (see e.g, extended release of a therapeutic protein in U.S. Patent Publication No. US20130129830, herein incorporated by reference in its entirety).

The microparticle for use with the present invention may have a diameter of at least 1 micron to at least 100 microns (e.g., at least 1 micron, at least 5 micron, at least 10 micron, at least 15 micron, at least 20 micron, at least 25 micron, at least 30 micron, at least 35 micron, at least 40 micron, at least 45 micron, at least 50 micron, at least 55 micron, at least 60 micron, at least 65 micron, at least 70 micron, at least 75 micron, at least 80 micron, at least 85 micron, at least 90 micron, at least 95 micron, at least 97 micron, at least 99 micron, and at least 100 micron).

NanoJackets and NanoLiposomes

The NAVs disclosed herein may be formulated in NanoJackets and NanoLiposomes by Keystone Nano (State College, Pa.). NanoJackets are made of compounds that are naturally found in the body including calcium, phosphate and may also include a small amount of silicates. Nanojackets may range in size from 5 to 50 nm and may be used to deliver hydrophilic and hydrophobic compounds such as, but not limited to, NAVs.

NanoLiposomes are made of lipids such as, but not limited to, lipids which naturally occur in the body. NanoLiposomes may range in size from 60-80 nm and may be used to deliver hydrophilic and hydrophobic compounds such as, but not limited to, NAVs. In one aspect, the NAVs disclosed herein are formulated in a NanoLiposome such as, but not limited to, Ceramide NanoLiposomes.

Pseudovirions

In one embodiment, the NAVs disclosed herein may be formulated in Pseudovirions (e.g., pseudo-virions). As a non-limiting example, the pseudovirions may be those developed and/or are described by Aura Biosciences (Cambridge, Mass.). In one aspect, the pseudovirion may be developed to deliver drugs to keratinocytes and basal membranes (See e.g., US Patent Publication Nos. US20130012450, US20130012566, US21030012426 and US20120207840 and International Publication No. WO2013009717, each of which is herein incorporated by reference in its entirety).

In one embodiment, the pseudovirion used for delivering the NAVs of the present invention may be derived from viruses such as, but not limited to, herpes and papillomaviruses (See e.g., US Patent Publication Nos. US Patent Publication Nos. US20130012450, US20130012566, US21030012426 and US20120207840 and International Publication No. WO2013009717, each of which is herein incorporated by reference in its entirety; and Ma et al. HPV pseudovirions as DNA delivery vehicles. Ther Deliv. 2011: 2(4): 427-430; Kines et al. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. PNAS 2009:106(48), 20458-20463; Roberts et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan.

Nature Medicine. 2007:13(7) 857-861; Gordon et al., Targeting the Vaginal Mucosa with Human Papillomavirus Psedudovirion Vaccines delivering SIV DNA. J Immunol. 2012 188(2) 714-723; Cuburu et al., Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses. The Journal of Clinical Investigation. 2012: 122(12) 4606-4620; Hung et al., Ovarian Cancer Gene Therapy Using HPV-16 Psedudovirion Carrying the HSV-tk Gene. PLoS ONE. 2012: 7(7) e40983; Johnson et al., Role of Heparan Sulfate in Attachment to and Infection of the Murine Femal Genital Tract by Human Papillomavirus. J Virology. 2009: 83(5) 2067-2074; each of which is herein incorporated by reference in its entirety).

The pseudovirion may be a virus-like particle (VLP) prepared by the methods described in US Patent Publication No. US20120015899 and US20130177587 and International Patent Publication No. WO2010047839 WO2013116656, WO2013106525 and WO2013122262, the contents of each of which is herein incorporated by reference in its entirety. In one aspect, the VLP may be, but is not limited to, bacteriophages MS, Qβ, R17, fr, GA, Sp, MI, I, MXI, NL95, AP205, f2, PP7, and the plant viruses Turnip crinkle virus (TCV), Tomato bushy stunt virus (TBSV), Southern bean mosaic virus (SBMV) and members of the genus Bromovirus including Broad bean mottle virus, Brome mosaic virus, Cassia yellow blotch virus, Cowpea chlorotic mottle virus (CCMV), Melandrium yellow fleck virus, and Spring beauty latent virus. In another aspect, the VLP may be derived from the influenza virus as described in US Patent Publication No. US20130177587 or U.S. Pat. No. 8,506,967, the contents of each of which are herein incorporated by reference in its entirety. In yet another aspect, the VLP may comprise a B7-1 and/or B7-2 molecule anchored to a lipid membrane or the exterior of the particle such as described in International Patent Publication No. WO2013116656, the contents of which are herein incorporated by reference in its entirety. In one aspect, the VLP may be derived from norovirus, rotavirus recombinant VP6 protein or double layered VP2/VP6 such as the VLP described in International Patent Publication No. WO2012049366, the contents of which are herein incorporated by reference in its entirety.

The pseudovirion may be a human papilloma virus-like particle such as, but not limited to, those described in International Publication No. WO2010120266 and US Patent Publication No. US20120171290, each of which is herein incorporated by reference in its entirety and Ma et al. HPV pseudovirions as DNA delivery vehicles. Ther Deliv. 2011: 2(4): 427-430; Kines et al. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. PNAS 2009:106(48), 20458-20463; Roberts et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nature Medicine. 2007:13(7) 857-861; Gordon et al., Targeting the Vaginal Mucosa with Human Papillomavirus Psedudovirion Vaccines delivering SIV DNA. J Immunol. 2012 188(2) 714-723; Cuburu et al., Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses. The Journal of Clinical Investigation. 2012: 122(12) 4606-4620; Hung et al., Ovarian Cancer Gene Therapy Using HPV-16 Psedudovirion Carrying the HSV-tk Gene. PLoS ONE. 2012: 7(7) e40983; Johnson et al., Role of Heparan Sulfate in Attachment to and Infection of the Murine Femal Genital Tract by Human Papillomavirus. J Virology. 2009: 83(5) 2067-2074; each of which is herein incorporated by reference in its entirety.

In one aspect, the pseudovirions may be virion derived nanoparticles such as, but not limited to, those described in US Patent Publication No. US20130116408 and US20130115247, each of which is herein incorporated by reference in their entirety. As a non-limiting example, the virion derived nanoparticles may be used to deliver NAVs which may be used in the treatment for cancer and/or enhance the immune system's recognition of the tumor. As a non-limiting example, the virion-derived nanoparticle which may selectively deliver an agent to at least one tumor may be the papilloma-derived particles described in International Patent Publication No. WO2013119877, the contents of which are herein incorporated by reference in its entirety. The virion derived nanoparticles may be made by the methods described in US Patent Publication No. US20130116408 and US20130115247 or International Patent Publication No. WO2013119877, each of which is herein incorporated by reference in their entirety.

In one embodiment, the virus-like particle (VLP) may be a self-assembled particle. Non-limiting examples of self-assembled VLPs and methods of making the self-assembled VLPs are described in International Patent Publication No. WO2013122262, the contents of which are herein incorporated by reference in its entirety.

Minicells

In one aspect, the NAVs may be formulated in bacterial minicells. As a non-limiting example, bacterial minicells may be those described in International Publication No. WO2013088250 or US Patent Publication No. US20130177499, the contents of each of which are herein incorporated by reference in its entirety. The bacterial minicells comprising therapeutic agents such as NAVs described herein may be used to deliver the therapeutic agents to brain tumors.

Semi-Solid Compositions

In one embodiment, the NAVs may be formulated with a hydrophobic matrix to form a semi-solid composition. As a non-limiting example, the semi-solid composition or paste-like composition may be made by the methods described in International Patent Publication No WO201307604, herein incorporated by reference in its entirety. The semi-solid composition may be a sustained release formulation as described in International Patent Publication No WO201307604, herein incorporated by reference in its entirety.

In another embodiment, the semi-solid composition may further have a micro-porous membrane or a biodegradable polymer formed around the composition (see e.g., International Patent Publication No WO201307604, herein incorporated by reference in its entirety).

The semi-solid composition using the NAVs of the present invention may have the characteristics of the semi-solid mixture as described in International Patent Publication No WO201307604, herein incorporated by reference in its entirety (e.g., a modulus of elasticity of at least 10⁻⁴ N·mm⁻², and/or a viscosity of at least 100 mPa·s).

Exosomes

In one embodiment, the NAVs may be formulated in exosomes. The exosomes may be loaded with at least one NAV and delivered to cells, tissues and/or organisms. As a non-limiting example, the NAVs may be loaded in the exosomes described in International Publication No. WO2013084000, herein incorporated by reference in its entirety.

Silk-Based Delivery

In one embodiment, the NAVs may be formulated in a sustained release silk-based delivery system. The silk-based delivery system may be formed by contacting a silk fibroin solution with a therapeutic agent such as, but not limited to, the NAVs described herein and/or known in the art. As a non-limiting example, the sustained release silk-based delivery system which may be used in the present invention and methods of making such system are described in US Patent Publication No. US20130177611, the contents of which are herein incorporated by reference in its entirety.

Microparticles

In one embodiment, formulations comprising NAVs may comprise microparticles. The microparticles may comprise a polymer described herein and/or known in the art such as, but not limited to, poly(α-hydroxy acid), a polyhydroxy butyric acid, a polycaprolactone, a polyorthoester and a polyanhydride. The microparticle may have adsorbent surfaces to adsorb biologically active molecules such as NAVs. As a non-limiting example microparticles for use with the present invention and methods of making microparticles are described in US Patent Publication No. US2013195923 and US20130195898 and U.S. Pat. Nos. 8,309,139 and 8,206,749, the contents of each of which are herein incorporated by reference in its entirety.

In another embodiment, the formulation may be a microemulsion comprising microparticles and NAVs. As a non-limiting example, microemulsions comprising microparticles are described in US Patent Publication No. US2013195923 and US20130195898 and U.S. Pat. Nos. 8,309,139 and 8,206,749, the contents of each of which are herein incorporated by reference in its entirety.

Amino Acid Lipids

In one embodiment, the NAVs may be formulated in amino acid lipids. Amino acid lipids are lipophilic compounds comprising an amino acid residue and one or more lipophilic tails. Non-limiting examples of amino acid lipids and methods of making amino acid lipids are described in U.S. Pat. No. 8,501,824, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the amino acid lipids have a hydrophilic portion and a lipophilic portion. The hydrophilic portion may be an amino acid residue and a lipophilic portion may comprise at least one lipophilic tail.

In one embodiment, the amino acid lipid formulations may be used to deliver the NAVs to a subject.

In another embodiment, the amino acid lipid formulations may deliver a NAV in releasable form which comprises an amino acid lipid that binds and releases the NAV. As a non-limiting example, the release of the NAVs may be provided by an acid-labile linker such as, but not limited to, those described in U.S. Pat. Nos. 7,098,032, 6,897,196, 6,426,086, 7,138,382, 5,563,250, and 5,505,931, the contents of each of which are herein incorporated by reference in its entirety.

Microvesicles

In one embodiment, NAVs may be formulated in microvesicles. Non-limiting examples of microvesicles include those described in US Patent Publication No. US20130209544, the contents of which are herein incorporated by reference in its entirety.

In one embodiment, the microvesicle is an ARRDC1-mediated microvesicles (ARMMs). Non-limiting examples of ARMMs and methods of making ARMMs are described in International Patent Publication No. WO2013119602, the contents of which are herein incorporated by reference in its entirety.

Interpolyelectrolyte Complexes

In one embodiment, the NAVs may be formulated in an interpolyelectrolyte complex. Interpolyelectrolyte complexes are formed when charge-dynamic polymers are complexed with one or more anionic molecules. Non-limiting examples of charge-dynamic polymers and interpolyelectrolyte complexes and methods of making interpolyelectrolyte complexes are described in U.S. Pat. No. 8,524,368, the contents of which is herein incorporated by reference in its entirety.

Cyrstalline Polymeric Systems

In one embodiment, the NAVs may be formulated in crystalline polymeric systems. Crystalline polymeric systems are polymers with crystalline moieties and/or terminal units comprising crystalline moieties. Non-limiting examples of polymers with crystalline moieties and/or terminal units comprising crystalline moieties termed “CYC polymers,” crystalline polymer systems and methods of making such polymers and systems are described in U.S. Pat. No. 8,524,259, the contents of which are herein incorporated by reference in its entirety.

Excipients

NAV pharmaceutical formulations may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but are not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, flavoring agents, stabilizers, antioxidants, osmolality adjusting agents, pH adjusting agents and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21^(st) Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.

In some embodiments, a pharmaceutically acceptable excipient may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use for humans and for veterinary use. In some embodiments, an excipient may be approved by United States Food and Drug Administration. In some embodiments, an excipient may be of pharmaceutical grade. In some embodiments, an excipient may meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia.

Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions. The composition may also include excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents.

Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.

Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, etc., and/or combinations thereof.

Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGUM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [TWEEN®20], polyoxyethylene sorbitan [TWEEN®60], polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate [SPAN®40], sorbitan monostearate [SPAN®60], sorbitan tristearate [SPAN®65], glyceryl monooleate, sorbitan monooleate [SPAN®80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [MYRJ®45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and SOLUTOL®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [BRIJ®30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLUORINC®F 68, POLOXAMER®188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.

Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); amino acids (e.g., glycine); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM®), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; etc.; and combinations thereof.

Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives. Oxidation is a potential degradation pathway for mRNA, especially for liquid mRNA formulations. In order to prevent oxidation, antioxidants can be added to the formulation. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, benzyl alcohol, butylated hydroxyanisole, EDTA, m-cresol, methionine, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, thioglycerol and/or sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS®, PHENONIP®, methylparaben, GERMALL®115, GERMABEN®II, NEOLONE™, KATHON™, and/or EUXYL®.

In some embodiments, the pH of the NAV solutions are maintained between pH 5 and pH 8 to improve stability. Exemplary buffers to control pH may include, but are not limited to sodium phosphate, sodium citrate, sodium succinate, histidine (or histidine-HCl), sodium carbonate, and/or sodium malate. In another embodiment, the exemplary buffers listed above may be used with additional monovalent counterions (including, but not limited to potassium). Divalent cations may also be used as buffer counterions; however, these are not preferred due to complex formation and/or mRNA degradation.

Exemplary buffering agents may also include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and/or combinations thereof.

Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof.

Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator.

Exemplary additives include physiologically biocompatible buffers (e.g., trimethylamine hydrochloride), addition of chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide), or, optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate). In addition, antioxidants and suspending agents can be used.

Cryoprotectants

In some embodiments, NAV formulations may comprise cyroprotectants. As used herein, there term “cryoprotectant” refers to one or more agent that when combined with a given substance, helps to reduce or eliminate damage to that substance that occurs upon freezing. In some embodiments, cryoprotectants are combined with NAVs in order to stabilize them during freezing. Frozen storage of NAVs between −20° C. and −80° C. may be advantageous for long term (e.g. 36 months) stability of polynucleotide. In some embodiments, cryoprotectants are included in NAV formulations to stabilize polynucleotide through freeze/thaw cycles and under frozen storage conditions. Cryoprotectants of the present invention may include, but are not limited to sucrose, trehalose, lactose, glycerol, dextrose, raffinose and/or mannitol. Trehalose is listed by the Food and Drug Administration as being generally regarded as safe (GRAS) and is commonly used in commercial pharmaceutical formulations.

Bulking Agents

In some embodiments, NAV formulations may comprise bulking agents. As used herein, ther term “bulking agent” refers to one or more agents included in formulations to impart a desired consistency to the formulation and/or stabilization of formulation components. In some embodiments, bulking agents are included in lyophilized NAV formulations to yield a “pharmaceutically elegant” cake, stabilizing the lyophilized NAVs during long term (e.g. 36 month) storage. Bulking agents of the present invention may include, but are not limited to sucrose, trehalose, mannitol, glycine, lactose and/or raffinose. In some embodiments, combinations of cryoprotectants and bulking agents (for example, sucrose/glycine or trehalose/mannitol) may be included to both stabilize NAVs during freezing and provide a bulking agent for lyophilization.

Non-limiting examples of formulations and methods for formulating the NAVs of the present invention are also provided in International Publication No WO2013090648 filed Dec. 14, 2012, the contents of which are incorporated herein by reference in their entirety.

Inactive Ingredients

In some embodiments, NAV formulations may comprise at least one excipient which is an inactive ingredient. As used herein, ther term “inactive ingredient” refers to one or more inactive agents included in formulations. In some embodiments, all, none or some of the inactive ingredients which may be used in the formulations of the present invention may be approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients and the routes of administration the inactive ingredients may be formulated in are described in Table 26. In Table 26, “AN” means anesthetic, “CNBLK” means cervical nerve block, “NBLK” means nerve block, “IV” means intravenous, “IM” means intramuscular and

“SC” means subcutaneous

TABLE 26 Inactive Ingredients Inactive Ingredient Route of Administration Alpha-Terpineol Topical Alpha-Tocopherol Intravenous; Topical Alpha-Tocopherol Acetate, Dl- Topical Alpha-Tocopherol, Dl- Intravenous; Topical 1,2,6-Hexanetriol Topical 1,2-Dimyristoyl-Sn-Glycero-3-(Phospho-S- Intravenous; Infusion (IV) (1-Glycerol)) 1,2-Dimyristoyl-Sn-Glycero-3- Intravenous; Infusion (IV) Phosphocholine 1,2-Dioleoyl-Sn-Glycero-3-Phosphocholine Epidural 1,2-Dipalmitoyl-Sn-Glycero-3-(Phospho- Epidural Rac-(1-Glycerol)) 1,2-Distearoyl-Sn-Glycero-3-(Phospho-Rac- Intravenous (1-Glycerol)) 1,2-Distearoyl-Sn-Glycero-3-Phosphocholine Intravenous 1-O-Tolylbiguanide Topical 2-Ethyl-1,6-Hexanediol Topical Acetic Acid Infiltration; Auricular (Otic); Extracorporeal; Intramuscular; Intravenous; Subcutaneous; Intra- articualr; Intralesional; Intramuscular; Intrasynovial; Intratracheal; Intravenous; Irrigation; Infusion (IV); Nasal; Nerve block; Ophthalmic; Photopheresis; Soft Tissue; Submucosal; Topical Acetic Acid, Glacial Intravenous; Infusion (IV); Subcutaneous Acetic Anhydride Intravenous Acetone Implantation; Topical Acetone Sodium Bisulfite Intrathecal (AN, CNBLK); Infiltration (AN); Dental; Inhalation; Nerve Block Acetylated Lanolin Alcohols Topical Acetylated Monoglycerides Intravenous Acetylcysteine Inhalation Acetyltryptophan, DL- Intravenous Acrylates Copolymer Topical; Transdermal Acrylic Acid-Isooctyl Acrylate Copolymer Transdermal Acrylic Adhesive 788 Transdermal Activated Charcoal Intramuscular; Intravenous; Irrigation; Infusion (IV) Adcote 72A103 Transdermal Adhesive Tape Topical Adipic Acid Intramuscular; Vaginal Aerotex Resin 3730 Transdermal Alanine Infusion (IV) Albumin Aggregated Intravenous Albumin Colloidal Intravenous Albumin Human Intravenous; Infusion (IV); Subcutaneous Alcohol Dental; Intramuscular; Intravenous; Subcutaneous; Inhalation; Intravascular; Infusion (IV); Ophthalmic; Rectal; Respiratory (Inhalation); Topical; Transdermal Alcohol, Dehydrated Dental; Extracorporeal; Intramuscular; Intravenous; Subcutaneous; Inhalation; Intracavitary; Intravascular; Intravesical; Nasal, Ophthalmic; Photopheresis, Rectal; Respiratory (Inhalation); Sublingual; Topical; Transdermal Alcohol, Denatured Denatal; Intravenous; Topical; Vaginal Alcohol, Diluted Intramuscular; Intravenous; Topical Alfadex Intracavitary Alginic Acid Ophthalmic Alkyl Ammonium Sulfonic Acid Betaine Topical Alkyl Aryl Sodium Sulfonate Topical Allantoin Topical; Vaginal Allyl .Alpha.-Ionone Nasal Almond Oil Topical Aluminum Acetate Auricular (Otic); Topical Aluminum Chlorhydroxy Allantoinate Topical Aluminum Hydroxide Topical Aluminum Hydroxide - Sucrose, Hydrated Topical Aluminum Hydroxide Gel Topical Aluminum Hydroxide Gel F 500 Topical Aluminum Hydroxide Gel F 5000 Topical Aluminum Monostearate Topical Aluminum Oxide Topical Aluminum Polyester Transdermal Aluminum Silicate Topical Aluminum Starch Octenylsuccinate Topical Aluminum Stearate Topical Aluminum Subacetate Rectal Aluminum Sulfate Anhydrous Auricular (Otic); Topical Amerchol C Topical Amerchol-Cab Ophthalmic, Topical Aminomethylpropanol Topical Ammonia Inhalation Ammonia Solution Topical Ammonia Solution, Strong Topical Ammonium Acetate Intramuscular; Intravenous; Infusion (IV) Ammonium Hydroxide Intravenous; Ophthalmic; Subcutaneous; Topical Ammonium Lauryl Sulfate Topical Ammonium Nonoxynol-4 Sulfate Topical Ammonium Salt Of C-12-C-15 Linear Topical Primary Alcohol Ethoxylate Ammonium Sulfate Intravenous Ammonyx Topical Amphoteric-2 Topical Amphoteric-9 Topical Anethole Dental Anhydrous Citric Acid Intravenous; Infusion (IV); Rectal; Topical Anhydrous Dextrose Intramuscular; Intravenous; Subcutaneous; Infusion (IV); Nasal; Spinal Anhydrous Lactose Intramuscular, Intravenous, Intracavitary, Intravenous; Infusion (IV); Vaginal Anhydrous Trisodium Citrate Intramuscular; Intravenous; Intra-arterial; Intra- articular; Intrabursal; Infusion (IV); Nasal; Ophthalmic, Soft Tissue, Topical Aniseed Oil Rectal Anoxid Sbn Topical Antifoam Topical Antipyrine Ophthalmic Apaflurane Respiratory (Inhalation) Apricot Kernel Oil Peg-6 Esters Topical; Vaginal Aquaphor Topical Arginine Intramuscular; Intravenous; Infusion (IV) Arlacel Topical Ascorbic Acid Infiltration (AN); Caudal Block; Epidural; Intramuscular; Intravenous; Inhalation; Infusion (IV); Nerve Block; Rectal; Subctaneous; Topical Ascorbyl Palmitate Rectal; Topical Aspartic Acid Infusion (IV) Balsam Peru Rectal Barium Sulfate Intrauterine; Vaginal Beeswax Topical; Vaginal Beeswax, Synthetic Topical Beheneth-10 Topical Bentonite Topical, Transdermal, Vaginal Benzalkonium Chloride Auricular (Otic); Inhalation; Intra-Articular; Intrabursal; Intradermal; Intralesional; Intramuscular; Intraocular; Nasal; Ophthalmic; Respiratory (Inhalation); Topical Benzenesulfonic Acid Intravenous; Infusion (IV) Benzethonium Chloride Auricular (Otic); Intramuscular; Intravenous; Infusion (IV); Nasal; Ophthalmic Benzododecinium Bromide Ophthalmic Benzoic Acid Intramuscular; Intravenous; Irrigation; Infusion (IV); Rectal; Topical; Vaginal Benzyl Alcohol Infiltration (AN); Auricular (Otic); Dental; Epidural; Extracorporeal; Interstitial; Intra-Arterial; Intra- Articular; Intrabursal; Intracavitary; Intradermal; Intralesional; Intramuscular; Intraperitoneal; Intrapleural; Intrasynovial; Intrathecal; Intratracheal; Intratumor; Intravenous; Infusion(IV); Nasal; Nerve Block; Rectal; Soft Tissue; Subconjunctival; Subcutaneous; Topical; Ureteral; Vaginal Benzyl Benzoate Intramuscular Benzyl Chloride Intravenous Betadex Topical Bibapcitide Intravenous Bismuth Subgallate Rectal Boric Acid Auricular (Otic); Intravenous; Ophthalmic; Topical Brocrinat Infusion (IV) Butane Topical Butyl Alcohol Topical Butyl Ester Of Vinyl Methyl Ether/Maleic Topical Anhydride Copolymer (125000 Mw) Butyl Stearate Topical Butylated Hydroxyanisole Intramuscular; Infusion (IV); Nasal; Rectal; Topical; Vaginal Butylated Hydroxytoluene Intramuscular; Intravenous; Infusion (IV); Nasal; Rectal; Topical; Transdermal; Vaginal Butylene Glycol Topical; Transdermal Butylparaben Intramuscular; Rectal; Topical Butyric Acid Transdermal C20-40 Pareth-24 Topical Caffeine Nasal; Ophthalmic Calcium Intramuscular Calcium Carbonate Auricular (Otic); Respiratory (Inhalation) Calcium Chloride Infiltration (AN); Caudal Block; Epidural; Intramuscular; Intravenous; Intraocular; Intraperitoneal; Intravascular; Intravitreal; Nerve Block; Ophthalmic; Subctaneous; Topical Calcium Gluceptate Intravenous Calcium Hydroxide Intravenous; Subcutaneous; Topical Calcium Lactate Vaginal Calcobutrol Intravenous Caldiamide Sodium Intravenous Caloxetate Trisodium Intravenous Calteridol Calcium Intravenous Canada Balsam Topical Caprylic/Capric Triglyceride Topical; Transdermal Caprylic/Capric/Stearic Triglyceride Topical Captan Topical Captisol Intravenous Caramel Rectal; Topical Carbomer 1342 Ophthalmic; Topical; Transdermal Carbomer 1382 Topical Carbomer 934 Rectal; Topical; Vaginal Carbomer 934p Ophthalmic; Rectal; Topical; Vaginal Carbomer 940 Ophthalmic; Topical; Transdermal Carbomer 941 Topical Carbomer 980 Topical; Transdermal Carbomer 981 Topical Carbomer Homopolymer Type B (Allyl Ophthalmic; Topical Pentaerythritol Crosslinked) Carbomer Homopolymer Type C (Allyl Topical Pentaerythritol Crosslinked) Carbon Dioxide Infiltration (AN); Intramuscular (IM); Infusion (IV); Inhalation; Intra-arterial; Intracardiac; Intrathecal; Intravascular; Intravenous Carboxy Vinyl Copolymer Topical Carboxymethylcellulose Intra-articular; Intrabursal; Intralesional; Intramuscular; Soft tissue; Topical Carboxymethylcellulose Sodium Dental; Intra-articular; Intrabursal; Intradermal; Intramuscular; Intrasynovial; Intratracheal; Nasal; Ophthalmic; Soft tissue; Subcutaneous; Topical Carboxypolymethylene Rectal; Topical Carrageenan Dental; Topical; Transdermal Carrageenan Salt Topical Castor Oil Intramuscular; Ophthalmic; Topical Cedar Leaf Oil Topical Cellulose Topical Cellulose, Microcrystalline Intra-articular; Intramuscular; Intravenous; Intravitreal; Nasal; Vaginal Cerasynt-Se Rectal; Topical Ceresin Topical Ceteareth-12 Topical Ceteareth-15 Topical Ceteareth-30 Topical Cetearyl Alcohol/Ceteareth-20 Topical Cetearyl Ethylhexanoate Topical Ceteth-10 Topical Ceteth-2 Topical Ceteth-20 Topical; Vaginal Ceteth-23 Topical Cetostearyl Alcohol Topical; Vaginal Cetrimonium Chloride Topical Cetyl Alcohol Auricular (Otic); Ophthalmic; Rectal; Topical; Vaginal Cetyl Esters Wax Topical; Vaginal Cetyl Palmitate Topical; Vaginal Cetylpyridinium Chloride Inhalation; Iontophoresis; Transdermal Chlorobutanol Infiltration (AN); Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Intravenous; Nasal; Nerve Block; Ophthalmic; Topical Chlorobutanol Hemihydrate Intramuscular; Intravenous Chlorobutanol, Anhydrous Intramuscular; Intravenous; Ophthalmic Chlorocresol Topical Chloroxylenol Auricular (Otic); Topical Cholesterol Epidural; Infiltration; Intravecous; Ophthalmic; Topical; Vaginal Choleth Vaginal Choleth-24 Topical Citrate Intravenous Citric Acid Intrathecal (AN, CNBLK); Infiltration (AN); Auricular (Otic); Caudal Block; Epidural; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Infiltration; Inhalation; Intra-amniotic; Intra- arterial; Intra-articular; Intrabursal; Intracardiac; Intralesional; Iintrapleural; Intrasynovial; Intrathecal; Intravascular; Intravenous; Iontophoresis; Nasal; Nerve Block; Ophthalmic; Peridural; Soft tissue; Topical; Transdermal; Vaginal Citric Acid Monohydrate Infiltration (AN); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intracardiac; Intraocular; Intravenous; Nasal; Nerve Block; Ophthalmic; Topical; Vaginal Citric Acid, Hydrous Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intravenous Cocamide Ether Sulfate Topical Cocamine Oxide Topical Coco Betaine Topical Coco Diethanolamide Topical Coco Monoethanolamide Topical Cocoa Butter Rectal; Topical Coco-Glycerides Topical Coconut Oil Topical Coconut Oil, Hydrogenated Rectal Coconut Oil/Palm Kernel Oil Glycerides, Rectal; Vaginal Hydrogenated Cocoyl Caprylocaprate Topical Cola Nitida Seed Extract Rectal Collagen Topical Coloring Suspension Topical Corn Oil Intramuscular Cottonseed Oil Intramuscular Cream Base Topical Creatine Intra-articular; Intralesional; Intramuscular Creatinine Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intra-articular; Intrabursal; Intradermal; Intralesional; Intrasynovial; Ophthalmic; Soft tissue; Topical Cresol Subcutaneous Croscarmellose Sodium Intramuscular Crospovidone Implantation; Intra-articluar; Intramuscular; Intrauterine; Topical; Transdermal; Vagiinal Cupric Sulfate Auricular (Otic) Cupric Sulfate Anhydrous Auricular (Otic) Cyclomethicone Topical Cyclomethicone/Dimethicone Copolyol Topical Cysteine Intramuscular (IM); Subcutaneous (SC); Intravenous; Infusion (IV) Cysteine Hydrochloride Intravenous; Infusion (IV) Cysteine Hydrochloride Anhydrous Intradiscal Cysteine, Dl- Intradiscal D&C Red No. 28 Topical D&C Red No. 33 Topical D&C Red No. 36 Topical D&C Red No. 39 Topical D&C Yellow No. 10 Dental; Inhalation; Rectal; Topical Dalfampridine Intravenous Daubert 1-5 Pestr (Matte) 164z Transdermal Decyl Methyl Sulfoxide Topical Dehydag Wax Sx Topical Dehydroacetic Acid Topical Dehymuls E Topical Denatonium Benzoate Topical Deoxycholic Acid Infusion (IV) Dextran Intravenous Dextran 40 Intravenous Dextrin Topical Dextrose Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Interstitial; Intracavitary; Intraperitoneal; Intrapleural; Intraspinal; Intravenous; Nasal; Spinal Dextrose Monohydrate Intravenous Dextrose Solution Intravenous; Infusion (IV) Diatrizoic Acid Intra-arterial; Intra-articular; Intracardiac; Intradiscal; Intramuscular; Intrauterine; Intravascular; Intravenous; Infusion (IV); Periarticular; Subcutaneous; Ureteral; Urethral Diazolidinyl Urea Topical Dichlorobenzyl Alcohol Topical Dichlorodifluoromethane Inhalation; Intrapleural; Nasal; Rectal; Topical Dichlorotetrafluoroethane Inhalation; Nasal; Rectal; Topical Diethanolamine Infusion (IV); Ophthalmic; Topical Diethyl Pyrocarbonate Infiltration Diethyl Sebacate Topical Diethylene Glycol Monoethyl Ether Topical; Transdermal Diethylhexyl Phthalate Ophthalmic; Transdermal Dihydroxyaluminum Aminoacetate Topical Diisopropanolamine Topical Diisopropyl Adipate Topical Diisopropyl Dilinoleate Topical Dimethicone 350 Topical Dimethicone Copolyol Topical; Transermal Dimethicone Mdx4-4210 Transdermal Dimethicone Medical Fluid 360 Dental; Intravenous; Topical; Transdermal Dimethyl Isosorbide Topical Dimethyl Sulfoxide Infusion (IV); Subcutanous; Topical Dimethylaminoethyl Methacrylate - Butyl Transdermal Methacrylate - Methyl Methacrylate Copolymer Dimethyldioctadecylammonium Bentonite Rectal Dimethylsiloxane/Methylvinylsiloxane Implantation; Intrauterine Copolymer Dinoseb Ammonium Salt Topical Dipalmitoylphosphatidylglycerol, Dl- Infiltration Dipropylene Glycol Transdermal Disodium Cocoamphodiacetate Topical Disodium Laureth Sulfosuccinate Topical Disodium Lauryl Sulfosuccinate Topical Disodium Sulfosalicylate Topical Disofenin Topical Divinylbenzene Styrene Copolymer Ophthalmic Dmdm Hydantoin Topical Docosanol Topical Docusate Sodium Intramuscular; Topical Duro-Tak 280-2516 Transdermal Duro-Tak 387-2516 Transdermal Duro-Tak 80-1196 Transdermal Duro-Tak 87-2070 Transdermal Duro-Tak 87-2194 Transdermal Duro-Tak 87-2287 Percutaneous; Transdermal Duro-Tak 87-2296 Transdermal Duro-Tak 87-2888 Transdermal Duro-Tak 87-2979 Transdermal Edetate Calcium Disodium Infiltration (AN); Caudal Block; Epidural; Intramuscular (IM); Infusion (IV); Intra-articular; Intra-arterial; Intracardiac; Intradiscal; Intraperitoneal; Intrathecal; Intrauterine; Intravascular; Intravenous; Intravesical; Nerve Block; Periarticular; Rectal; Subcutaneous; Ureteral; Urethral Edetate Disodium Infiltration (AN), Auricular (Otic); Caudal Block; Epidural; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Intra-arterial; Intra- articular; Intrabursal; Intracardiac; Intradermal; Intradiscal; Intralesional; Intrasynovial; Intrauterine; Intravascular; Intravenous; Iontophoresis; Nasal; Nerve Block; Ophthalmic; Rectal; Respiratory (Inhalation); Soft tissue; Topical; Transdermal; Ureteral; Urethral; Vaginal Edetate Disodium Anhydrous Intra-amniotic; Intramuscular; Intravenous; Infusion (IV); Ophthalmic Edetate Sodium Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Ophthalmic; Topical Edetic Acid Auricular (Otic); Rectal; Submucosal; Topical Egg Phospholipids Intravenous; Infusion (IV) Entsufon Topical Entsufon Sodium Topical Epilactose Rectal Epitetracycline Hydrochloride Topical Essence Bouquet 9200 Topical Ethanolamine Hydrochloride Intravenous Ethyl Acetate Intramuscular; Topical; Transdermal Ethyl Oleate Transdermal Ethylcelluloses Topical; Transdermal; Vaginal Ethylene Glycol Topical Ethylene Vinyl Acetate Copolymer Implantation; Intrauerine; Ophthalmic; Periodontal; Subcutaneous; Transdermal Ethylenediamine Intravenous; Infusion (IV); Rectal; Topical Ethylenediamine Dihydrochloride Topical Ethylene-Propylene Copolymer Transdermal Ethylene-Vinyl Acetate Copolymer (28% Vaginal Vinyl Acetate) Ethylene-Vinyl Acetate Copolymer (9% Vaginal Vinylacetate) Ethylhexyl Hydroxystearate Topical Ethylparaben Topical Eucalyptol Dental Exametazime Intravenous Fat, Edible Rectal Fat, Hard Rectal Fatty Acid Esters Transdermal Fatty Acid Pentaerythriol Ester Topical Fatty Acids Topical Fatty Alcohol Citrate Topical Fatty Alcohols Vaginal Fd&C Blue No. 1 Dental; Rectal; Topical Fd&C Green No. 3 Dental; Rectal Fd&C Red No. 4 Topical Fd&C Red No. 40 Topical Fd&C Yellow No. 10 (Delisted) Topical Fd&C Yellow No. 5 Topical; Vaginal Fd&C Yellow No. 6 Inhalation; Rectal; Topical Ferric Chloride Intravenous Ferric Oxide Topical Flavor 89-186 Dental Flavor 89-259 Dental Flavor Df-119 Dental Flavor Df-1530 Dental Flavor Enhancer Dental Flavor Fig 827118 Rectal Flavor Raspberry Pfc-8407 Rectal Flavor Rhodia Pharmaceutical No. Rf 451 Topical Fluorochlorohydrocarbons Inhalation Formaldehyde Topical Formaldehyde Solution Topical Fractionated Coconut Oil Topical Fragrance 3949-5 Topical Fragrance 520a Topical Fragrance 6.007 Topical Fragrance 91-122 Topical Fragrance 9128-Y Topical Fragrance 93498g Topical Fragrance Balsam Pine No. 5124 Topical Fragrance Bouquet 10328 Topical Fragrance Chemoderm 6401-B Topical Fragrance Chemoderm 6411 Topical Fragrance Cream No. 73457 Topical Fragrance Cs-28197 Topical Fragrance Felton 066m Topical Fragrance Firmenich 47373 Topical Fragrance Givaudan Ess 9090/1c Topical Fragrance H-6540 Topical Fragrance Herbal 10396 Topical Fragrance Nj-1085 Topical Fragrance P O Fl-147 Topical Fragrance Pa 52805 Topical Fragrance Pera Derm D Topical Fragrance Rbd-9819 Topical Fragrance Shaw Mudge U-7776 Topical Fragrance Tf 044078 Topical Fragrance Ungerer Honeysuckle K 2771 Topical Fragrance Ungerer N5195 Topical Fructose Infusion (IV); Rectal Gadolinium Oxide Intravenous Galactose Rectal Gamma Cyclodextrin Intravenous Gelatin Dental; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intravenous; Respiratory (Inhalation); Topical; Vaginal Gelatin, Crosslinked Dental Gelfoam Sponge N/A Gellan Gum (Low Acyl) Ophthalmic Gelva 737 Transdermal Gentisic Acid Intravenous Gentisic Acid Ethanolamide Infusion (IV) Gluceptate Sodium Intravenous Gluceptate Sodium Dihydrate Intravenous Gluconolactone Intramuscular (IM); Infusion (IV); Intravesou; Topical Glucuronic Acid Intravenous Glutamic Acid, Dl- Vaginal Glutathione Intramuscular Glycerin Auricular (Otic); Dental; Intramuscular; Infusion (IV); Subcutaneous (SC); Inhalation; Intradermal; Intravenous; Iontophoresis; Nasal; Ophthalmic; Perfusion; Biliary; Rectal; Topical; Transdermal; Vaginal Glycerol Ester Of Hydrogenated Rosin Nasal Glyceryl Citrate Topical Glyceryl Isostearate Topical; Vaginal Glyceryl Laurate Transdermal Glyceryl Monostearate Topical; Vaginal Glyceryl Oleate Topical; Transdermal Glyceryl Oleate/Propylene Glycol Topical Glyceryl Palmitate Rectal; Topical Glyceryl Ricinoleate Topical Glyceryl Stearate Auricular (Otic); Dental; Ophthalmic; Rectal; Topical; Vaginal Glyceryl Stearate - Laureth-23 Topical Glyceryl Stearate/Peg Stearate Rectal Glyceryl Stearate/Peg-100 Stearate Topical Glyceryl Stearate/Peg-40 Stearate Rectal Glyceryl Stearate-Stearamidoethyl Topical Diethylamine Glyceryl Trioleate Epidural Glycine Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intravenous; Rectal; Respiratory (Inhalation) Glycine Hydrochloride Subcutaneous Glycol Distearate Topical Glycol Stearate Topical Guanidine Hydrochloride Intravenous Guar Gum Topical; Vaginal Hair Conditioner (18n195-1m) Topical Heptane Transdermal Hetastarch Intravenous Hexylene Glycol Topical High Density Polyethylene Dental; Intrauterine; Ophthalmic; Topical; Transdermal; Vaginal Histidine Intravenous; Infusion (IV); Subcutaneous Human Albumin Microspheres Intravenous Hyaluronate Sodium Intra-articular; Intramuscular; Intravitreal; Topical Hydrocarbon Rectal Hydrocarbon Gel, Plasticized Dental; Ophthalmic; Topical Hydrochloric Acid Intrathecal (AN, CNBLK); Infiltration (AN); Sympathetic (AN, NBLK); Auricular (Otic); Caudal Block; Dental; Diagnostic; Epidural; Extracorporeal; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Infiltration; Inhalationi; Interstitial; Intra- amniotic; Intra-arterial; Intra-articular; Intrabursal; Intracardiac; Intracaudal; Intracavitary; Intradermal; Intralesional; Intraocular; Intraperitoneal; Intrapleural; Intraspinal; Intrasynovial; Intrathecal; Intratracheal; Intratumor; Intravascular; Intravenous; Intravesical; Intravitreal; Iontophoresis; Irrigation; Nasal; Nerve Block, Ophthalmic; Parenteral; Perfusion, Cardiac; Peridural; Perineural; Periodontal; Pectal; Respiratory (Inhalation); Retrobulbar; Soft tissue; Spinal; Subarachnoid; Subconjunctival; Subcutaneous; Topical; Transdermal; Ureteral; Urethral Hydrochloric Acid, Diluted Infiltration (AN); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Intra-arterial; Intravascular; Intravenous; Nerve Block; Ophthalmic; Topical Hydrocortisone Auricular (Otic) Hydrogel Polymer Vaginal Hydrogen Peroxide Topical Hydrogenated Castor Oil Topical Hydrogenated Palm Oil Rectal; Vaginal Hydrogenated Palm/Palm Kernel Oil Peg-6 Topical Esters Hydrogenated Polybutene 635-690 Transdermal Hydroxide Ion Intramuscular; Infusion (IV) Hydroxyethyl Cellulose Auricular (Otic); Ophthalmic; Topical; Transdermal Hydroxyethylpiperazine Ethane Sulfonic Intravenous Acid Hydroxymethyl Cellulose Topical Hydroxyoctacosanyl Hydroxystearate Topical Hydroxypropyl Cellulose Topical Hydroxypropyl Methylcellulose 2906 Ophthalmic Hydroxypropyl-Bcyclodextrin Intravenous; Infusion (IV) Hypromellose 2208 (15000 Mpa · S) Vaginal Hypromellose 2910 (15000 Mpa · S) Nasal; Ophthalmic Hypromelloses Irrigation; Ophthalmic; Rectal; Topical; Vaginal Imidurea Topical Iodine Intra-arterial; Intra-articular; Intracardiac; Intradiscal; Intravascular; Intravenous; Periarticular Iodoxamic Acid Intravenous Iofetamine Hydrochloride Intravenous Irish Moss Extract Topical Isobutane Topical Isoceteth-20 Topical Isoleucine Infusion (IV) Isooctyl Acrylate Topical Isopropyl Alcohol Intravenous; Topical Isopropyl Isostearate Topical Isopropyl Myristate Auricular (Otic); Topical; Transdermal; Vaginal Isopropyl Myristate - Myristyl Alcohol Topical Isopropyl Palmitate Topical; Transdermal Isopropyl Stearate Topical Isostearic Acid Topical Isostearyl Alcohol Topical Isotonic Sodium Chloride Solution Epidural; Intratracheal; Intravenous; Infusion (IV) Jelene Ophthalmic; Topical Kaolin Topical Kathon Cg Topical Kathon Cg II Topical Lactate Topical Lactic Acid Infiltration (AN); Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intracardiac; Intravenous; Nerve Block; Topical; Vaginal Lactic Acid, Dl- Intramuscular (IM); Infusion (IV); Intravesou; Topical; Vaginal Lactic Acid, L- Intravenous; Subcutanous Lactobionic Acid Intravenous; Infusion (IV) Lactose Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Intracavitary; Intravenous; Rectal; Transdermal; Vaginal Lactose Monohydrate Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intracavitary; Intravenous; Respiratory (Inhalation); Vaginal Lactose, Hydrous Intramuscular (IM); Infusion (IV); Intravenous; Vaginal Laneth Topical Lanolin Ophthalmic; Rectal; Topical; Vaginal Lanolin Alcohol - Mineral Oil Topical Lanolin Alcohols Ophthalmic; Topical Lanolin Anhydrous Ophthalmic; Topical; Transdermal; Vaginal Lanolin Cholesterols Topical Lanolin Nonionic Derivatives Ophthalmic Lanolin, Ethoxylated Topical Lanolin, Hydrogenated Topical Lauralkonium Chloride Ophthalmic Lauramine Oxide Topical Laurdimonium Hydrolyzed Animal Collagen Topical Laureth Sulfate Topical Laureth-2 Topical Laureth-23 Topical Laureth-4 Topical Lauric Diethanolamide Topical Lauric Myristic Diethanolamide Topical Lauroyl Sarcosine Ophthalmic Lauryl Lactate Transdermal Lauryl Sulfate Topical Lavandula Angustifolia Flowering Top Topical Lecithin Inhalation; Intramuscular; Rectal; Topical; Transdermal; Vaginal Lecithin Unbleached Topical Lecithin, Egg Intravenous Lecithin, Hydrogenated Auricular (Otic) Lecithin, Hydrogenated Soy Inhalation; Intravenous Lecithin, Soybean Inhalation; Vaginal Lemon Oil Topical Leucine Infusion (IV) Levulinic Acid Transdermal Lidofenin Intravenous Light Mineral Oil Ophthalmic; Rectal; Topical; Vaginal; Transdermal Light Mineral Oil (85 Ssu) Topical Limonene, (+/−)- Topical Lipocol Sc-15 Topical Lysine Intramuscular (IM); Infusion (IV) Lysine Acetate Infusion (IV) Lysine Monohydrate Respiratory (Inhalation) Magnesium Aluminum Silicate Rectal; Topical; Vaginal Magnesium Aluminum Silicate Hydrate Rectal; Topical; Vaginal Magnesium Chloride Intramuscular; Intraocular; Intraperitoneal; Intravitreal; Infusion (IV); Ophthalmic; Subcutaneous Magnesium Nitrate Topical Magnesium Stearate Implantation; Intravitreal; Subcutaneous; Topical; Transmucosal; Vaginal Maleic Acid Intramuscular; Infusion (IV) Mannitol Intramuscular (IM); Infusion (IV); Subcutanous (SC); Intravenous; Ophthalmic; Parenteral; Respiratory (Inhalation); Submucosal; Topical; Transdermal Maprofix Topical Mebrofenin Intravenous Medical Adhesive Modified S-15 Transdermal Medical Antiform A-F Emulsion Topical Medronate Disodium Intravenous Medronic Acid Intravenous Meglumine Intra-arterial; Intra-articular; Intracardiac; Intradiscal; Intramuscular; Intrauterine; Intravascular; Intravenous; Infusion (IV); Periarticular; Ureteral; Urethral Menthol Detanl; Inhalation; Topical Metacresol Intramuscular (IM); Infusion (IV); Subcutanous (SC); Intradermal Metaphosphoric Acid Infusion (IV) Methanesulfonic Acid Intramuscular (IM); Infusion (IV); Subcutaneous (SC) Methionine Intramuscular; Intrathecal; Intravenous; Infusion (IV); Subcutaneous Methyl Alcohol Transdermal Methyl Gluceth-10 Topical Methyl Gluceth-20 Topical Methyl Gluceth-20 Sesquistearate Topical Methyl Glucose Sesquistearate Topical Methyl Laurate Transdermal Methyl Pyrrolidone Periodontal; Subcutaneous Methyl Salicylate Topical Methyl Stearate Topical; Vaginal Methylboronic Acid Intravenous Methylcellulose (4000 Mpa · S) Ophthalmic Methylcelluloses Intra-articular; Intralesional; Intramuscular; Intrasynovial; Nasal; Ophthalmic; Soft tissue; Topical Methylchloroisothiazolinone Topical Methylene Blue Intravenous Methylisothiazolinone Topical Methylparaben Infiltration (AN); Auricular (Otic); Caudal Block; Epidural; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Intra-arterial; Intra- articular; Intrabursal; Intradermal; Intralesional; Intrasynovial; Intravenous; Iontophoresis; Irrigation; Nasal; Nerve Block; Ophthalmic; Peridural; Rectal; Soft tissue; Topical; Ureteral; Urethral; Vaginal Microcrystalline Wax Topical; Vaginal Mineral Oil Auricular (Otic); Dental; Ophthalmic; Topical; Transdermal; Vaginal Mono And Diglyceride Topical Monostearyl Citrate Topical Monothioglycerol Infiltration (AN); Caudal Block; Epidural; Intramuscular (IM); Infusion (IV); Subcutanous (SC); Intravenous; Nerve Block Multisterol Extract Topical Myristyl Alcohol Topical Myristyl Lactate Topical Myristyl-.Gamma.-Picolinium Chloride Intra-articular; Intralesional; Intramuscular; Intrasynovial; Soft tissue N-(Carbamoyl-Methoxy Peg-40)-1,2- Intravenous Distearoyl-Cephalin Sodium N,N-Dimethylacetamide Intramuscular; Intravenous; Infusion (IV) Niacinamide Intramuscular; Infusion (IV); Intra-articular; Intralesional; Intrasynovial; Topical Nioxime Intravenous Nitric Acid Inhalation; Infusion (IV); Ophthalmic; Topical; Vaginal Nitrogen Infiltration (AN); Caudal Block; Dental; Epidural; Intramuscular; Infusion (IV); Subcutanous (SC); Inhalation; Intra-arterial; Intracavitary; Intramuscular (IM); Intrathecal; Intratumor; Intravascular; Intravenous; Intravesical; Irrigation; Nasal; Nerve Block; Ophthalmic; Parenteral; Submucosal; Topical; Transdermal Nonoxynol Iodine Topical Nonoxynol-15 Topical Nonoxynol-9 Ophthalmic; Topical Norflurane Inhalation; Nasal; Respiratory (Inhalation) Oatmeal Topical Octadecene-1/Maleic Acid Copolymer Topical Octanoic Acid Intravenous Octisalate Transdermal Octoxynol-1 Topical Octoxynol-40 Ophthalmic Octoxynol-9 Topical Octyldodecanol Topical; Transdermal; Vaginal Octylphenol Polymethylene Ophthalmic Oleic Acid Inhalation; Nasal; Respiratory (Inhalation); Topical; Transdermal Oleth-10/Oleth-5 Topical Oleth-2 Topical Oleth-20 Topical Oleyl Alcohol Topical; Transdermal Oleyl Oleate Topical; Transdermal Olive Oil Topical Oxidronate Disodium Intravenous Oxyquinoline Intravenous Palm Kernel Oil Rectal Palmitamine Oxide Topical Parabens Topical Paraffin Rectal; Topical Paraffin, White Soft Topical Parfum Creme 45/3 Topical Peanut Oil Intramuscular; Intratracheal; Topical; Vaginal Peanut Oil, Refined Topical Pectin Dental; Topical Peg 6-32 Stearate/Glycol Stearate Topical; Vaginal Peg Vegetable Oil Intramuscular (IM); Infusion (IV); Subcutaneous (SC) Peg-100 Stearate Topical; Vaginal Peg-12 Glyceryl Laurate Topical Peg-120 Glyceryl Stearate Topical; Vaginal Peg-120 Methyl Glucose Dioleate Topical Peg-15 Cocamine Topical Peg-150 Distearate Topical Peg-2 Stearate Topical; Vaginal Peg-20 Sorbitan Isostearate Intramuscular Peg-22 Methyl Ether/Dodecyl Glycol Topical Copolymer Peg-25 Propylene Glycol Stearate Topical Peg-4 Dilaurate Topical Peg-4 Laurate Topical Peg-40 Castor Oil Intramuscular (IM); Subcutaneous (SC); Infusion (IV) Peg-40 Sorbitan Diisostearate Dental Peg-45/Dodecyl Glycol Copolymer Topical Peg-5 Oleate Topical; Vaginal Peg-50 Stearate Topical Peg-54 Hydrogenated Castor Oil Topical Peg-6 Isostearate Topical Peg-60 Castor Oil Infusion (IV) Peg-60 Hydrogenated Castor Oil Topical Peg-7 Methyl Ether Topical Peg-75 Lanolin Topical Peg-8 Laurate Topical Peg-8 Stearate Topical Pegoxol 7 Stearate Topical; Vaginal Pentadecalactone Transdermal Pentaerythritol Cocoate Topical Pentasodium Pentetate Intravenous Pentetate Calcium Trisodium Intrathecal; Intravenous; Infusion (IV) Pentetic Acid Intrathecal; Intravenous Peppermint Oil Dental; Topical Perflutren Intravenous Perfume 25677 Topical Perfume Bouquet Topical Perfume E-1991 Topical Perfume Gd 5604 Topical Perfume Tana 90/42 Scba Topical Perfume W-1952-1 Topical Petrolatum Auricular (Otic); Ophthalmic; Topical Petrolatum, White Auricular (Otic); Dental; Nasal; Ophthalmic; Rectal; Topical; Transdermal; Vaginal Petroleum Distillates Topical Phenol Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intra-articular; Intradermal; Intralesional; Intrasynovial; Intravenous; Soft tissue Phenol, Liquefied Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intravenous Phenonip Iontophoresis; Topical Phenoxyethanol Topical Phenylalanine Infusion (IV) Phenylethyl Alcohol Auricular (Otic); Nasal; Ophthalmic Phenylmercuric Acetate Ophthalmic; Topical; Vaginal Phenylmercuric Nitrate Intramuscular; Ophthalmic Phosphatidyl Glycerol, Egg Intravenous Phospholipid Infusion (IV) Phospholipid, Egg Intravenous; Infusion (IV) Phospholipon 90g Vagianl Phosphoric Acid Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Infiltration; Intra-articular; Intralesional; Intravenous; Ophthalmic; Soft tissue; Topical; Vaginal Pine Needle Oil (Pinus Sylvestris) Topical Piperazine Hexahydrate Vagianl Plastibase-50w Dental; Topical Polacrilin Iontophoresis; Transdermal Polidronium Chloride Ophthalmic; Topical Poloxamer 124 Topical Poloxamer 181 Topical Poloxamer 182 Topical Poloxamer 188 Intravenous; Ophthalmic; Peridontal; Subcutaneous; Topical Poloxamer 237 Topical Poloxamer 407 Ophthalmic; Peridontal; Topical Poly(Bis(P-Carboxyphenoxy)Propane Implantation Anhydride): Sebacic Acid Poly(Dimethylsiloxane/Methylvinylsiloxane/ Vagianl Methylhydrogensiloxane) Dimethylvinyl Or Dimethylhydroxy Or Trimethyl Endblocked Poly(Dl-Lactic-Co-Glycolic Acid), (50:50 N/A Poly(Dl-Lactic-Co-Glycolic Acid), Ethyl N/A Ester Terminated, (50:50 Polyacrylic Acid (250000 Mw) Transdermal Polybutene (1400 Mw) Transdermal Polycarbophil Ophthalmic; Topical; Vaginal Polyester Transdermal; Vaginal Polyester Polyamine Copolymer Transdermal Polyester Rayon Transdermal Polyethylene Glycol 1000 Rectal; Respiratory (Inhalation); Topical; Vaginal Polyethylene Glycol 1450 Topical; Urethral Polyethylene Glycol 1500 Topical Polyethylene Glycol 1540 Dental; Rectal; Topical Polyethylene Glycol 200 Intramuscular; Topical Polyethylene Glycol 300 Intramuscular (IM); Infusion (IV); Intravenous; Ophthalmic; Topical Polyethylene Glycol 300-1600 Topical Polyethylene Glycol 3350 Intra-articular; Intralesional; Intramuscular; Intrasynovial; Nasal; Rectal; Soft tissue; Subcutaneous; Topical; Vaginal Polyethylene Glycol 400 Intramuscular (IM); Infusion (IV); Intravenous; Nasal; Ophthalmic; Rectal; Topical; Vaginal Polyethylene Glycol 4000 Intra-articular; Intralesional; Intramuscular; Intrasynovial; Rectal; Soft tissue; Topical; Vaginal Polyethylene Glycol 540 Topical Polyethylene Glycol 600 Intravenous; Topical Polyethylene Glycol 6000 Rectal; Topical; Vaginal Polyethylene Glycol 8000 Ophthalmic; Rectal; Topical; Vaginal Polyethylene Glycol 900 Topical Polyethylene High Density Containing Ferric Intrauterine Oxide Black (<1%) Polyethylene Low Density Containing Initrauterine Barium Sulfate (20-24%) Polyethylene T Initrauterine Polyethylene Terephthalates Transdermal Polyglactin Dental; Implantation; Intramuscular; Subcutaneous Polyglyceryl-3 Oleate Vagianl Polyglyceryl-4 Oleate Vagianl Polyhydroxyethyl Methacrylate Topical Polyisobutylene Topical; Transdermal Polyisobutylene (1100000 Mw) Topical; Transdermal Polyisobutylene (35000 Mw) Transdermal Polyisobutylene 178-236 Transdermal Polyisobutylene 241-294 Transdermal Polyisobutylene 35-39 Transdermal Polyisobutylene Low Molecular Weight Transdermal Polyisobutylene Medium Molecular Weight Transdermal Polyisobutylene/Polybutene Adhesive Transdermal Polylactide Intramuscular; Peridontal Polyols Dental Polyoxyethylene - Polyoxypropylene 1800 Ophthalmic; Topical Polyoxyethylene Alcohols Topical Polyoxyethylene Fatty Acid Esters Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Topical Polyoxyethylene Propylene Topical Polyoxyl 20 Cetostearyl Ether Topical Polyoxyl 35 Castor Oil Intravesical; Infusion (IV); Ophthalmic Polyoxyl 40 Hydrogenated Castor Oil Dental; Ophthalmic; Topical Polyoxyl 40 Stearate Auricular (Otic); Dental; Ophthalmic; Topical Polyoxyl 400 Stearate Nasal; Topical Polyoxyl 6 And Polyoxyl 32 Palmitostearate Topical Polyoxyl Distearate Topical Polyoxyl Glyceryl Stearate Topical Polyoxyl Lanolin Topical Polyoxyl Palmitate Vagianl Polyoxyl Stearate Auricular (Otic); Topical Polypropylene Intrauterine; Topical; Transdermal Polypropylene Glycol Intramuscular (IM); Infusion (IV); Ophthalmic Polyquaternium-10 Topical Polyquaternium-7 (70/30 N/A Acrylamide/Dadmac Polysiloxane Intravenous Polysorbate 20 Auricular (Otic); Intramuscular (IM); Subcutaneous (SC); Intravenous; Infusion (IV); Nasal; Ophthalmic; Topical; Vaginal Polysorbate 40 Intramuscular (IM); Infusion (IV); Topical Polysorbate 60 Ophthalmic; Rectal; Topical; Vaginal Polysorbate 65 Topical Polysorbate 80 Auricular (Otic); Intra-articular; Intrabursal; Intradermal; Intralesional; Intramuscular; Intrasynovial; Intravenous; Infusion (IV); Nasal; Ophthalmic; Rectal; Soft tissue; Subcutaneous; Topical; Vaginal Polyurethane Vagianl Polyvinyl Acetate Transdermal Polyvinyl Alcohol Auricular (Otic); Intramuscular; Intraocular; Intravitreal; Iontophoresis; Ophthalmic; Topical; Transdermal Polyvinyl Chloride Transdermal Polyvinyl Chloride-Polyvinyl Acetate Transdermal Copolymer Polyvinylpyridine Transdermal Poppy Seed Oil Intralymphatic; Intrauterine Potash Topical Potassium Acetate Ophthalmic; Rectal Potassium Alum Vagianl Potassium Bicarbonate Transmucosal Potassium Bisulfite Intravenous Potassium Chloride Infiltration (AN); Caudal Block; Epidural; Intraocular; Intravenous; Intravitreal; Infusion (IV); Nerve Block; Ophthalmic Potassium Citrate Topical Potassium Hydroxide Intravascular; Intravenous; Infusion (IV); Topical; Vaginal Potassium Metabisulfite Infiltration (AN); Auricular (Otic); Intramuscular (IM); Infusion (IV); Nerve Block; Rectal Potassium Phosphate, Dibasic Intra-articular; Intramuscular; Intravenous; Infusion (IV); Subcutaneous Potassium Phosphate, Monobasic Infiltration (AN); Auricular (Otic); Intramuscular (IM); Infusion (IV); Intra-articular; Intramuterine; Intravenous; Intravesical; Nasal; Nerve Block; Ophthalmic; Subcutaneous Potassium Soap Topical Potassium Sorbate Nasal; Ophthalmic; Topical Povidone Acrylate Copolymer Topical Povidone Hydrogel Iontophoresis; Topical Povidone K17 Subcutaneous Povidone K25 Respiratory (Inhalation) Povidone K29/32 Ophthalmic; Transdermal; Vaginal Povidone K30 Ophthalmic Povidone K90 Ophthalmic; Topical Povidone K90f Auricular (Otic) Povidone/Eicosene Copolymer Topical Povidones Auricular (Otic); Intramuscular; Intravenous; Infusion (IV); Ophthalmic; Subcutaneous; Topical; Transdermal; Vaginal Ppg-12/Smdi Copolymer Topical Ppg-15 Stearyl Ether Topical Ppg-20 Methyl Glucose Ether Distearate Topical Ppg-26 Oleate Topical Product Wat Topical Proline Infusion (IV) Promulgen D Topical; Vaginal Promulgen G Topical Propane Topical Propellant A-46 Topical Propyl Gallate Topical; Intramuscular Propylene Carbonate Topical Propylene Glycol Auricular (Otic); Dental; Extracorporeal; Intramuscular (IM); Infusion (IV); Inhalation; Intravenous; Nasal; Ophthalmic; Photopheresis; Rectal; Subcutaneous; Topical; Transdermal; Vaginal Propylene Glycol Diacetate Auricular (Otic); Topical Propylene Glycol Dicaprylate Topical Propylene Glycol Monolaurate Transdermal Propylene Glycol Monopalmitostearate Topical; Vaginal Propylene Glycol Palmitostearate Topical Propylene Glycol Ricinoleate Topical Propylene Glycol/Diazolidinyl Topical Urea/Methylparaben/Propylparben Propylparaben Infiltration (AN); Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Intra-arterial; Intra-articular; Intrabursal; Intralesional; Intrasynovial; Intravenous; Nasal; Nerve Block; Ophthalmic; Rectal; Soft tissue; Topical; Ureteral; Urethral; Vaginal Protamine Sulfate Intramuscular (IM); Subcutaneous (SC); Intradermal Protein Hydrolysate Topical Pvm/Ma Copolymer Dental Quaternium-15 Topical Quaternium-15 Cis-Form Topical; Vaginal Quaternium-52 Topical Ra-2397 Transdermal Ra-3011 Transdermal Saccharin Inhalation; Topical Saccharin Sodium Dental; Intramuscular (IM); Infusion (IV); Inhalation; Intravenous; Rectal; Topical Saccharin Sodium Anhydrous Intramuscular (IM); Infusion (IV); Rectal Safflower Oil Topical Sd Alcohol 3a Topical Sd Alcohol 40 Topical Sd Alcohol 40-2 Topical Sd Alcohol 40b Topical Sepineo P 600 Topical Serine Infusion (IV) Sesame Oil Intramuscular (IM); Subcutaneous (SC) Shea Butter Topical Silastic Brand Medical Grade Tubing Implantation Silastic Medical Adhesive, Silicone Type A Implantation Silica, Dental Dental Silicon Topical; Transdermal Silicon Dioxide Dental; Topical; Vaginal Silicon Dioxide, Colloidal Endocervical; Rectal; Respiratory (Inhalation); Transdermal; Vaginal Silicone Intramuscular (IM); Infusion (IV); Intrauterine; Topical; Transdermal; Vaginal Silicone Adhesive 4102 Percutaneous; Transdermal Silicone Adhesive 4502 Transdermal Silicone Adhesive Bio-Psa Q7-4201 Transdermal; Topical Silicone Adhesive Bio-Psa Q7-4301 Transdermal; Topical Silicone Emulsion Topical Silicone/Polyester Film Strip Transdermal Simethicone Intramuscular (IM); Infusion (IV); Rectal; Topical Simethicone Emulsion Topical Sipon Ls 20np Topical Soda Ash Ophthalmic Sodium Acetate Auricular (Otic); Extracorporeal; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Interstitial; Intra-articular; Intracavitary; Intradermal; Intralesional; Intraocular; Intraperitoneal; Intrapleural; Intrasynovial; Intravenous; Intravitreal; Nasal; Ophthalmic; Parenteral; Phtotpheresis; Soft tissue; Submucosal; Topical Sodium Acetate Anhydrous Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intravenous; Topical Sodium Alkyl Sulfate Topical Sodium Ascorbate Intravenous Sodium Benzoate Dental; Intramuscular (IM); Infusion (IV); Intravenous; Rectal; Topical Sodium Bicarbonate Intramuscular (IM); Infusion (IV); Intraperitoneal; Intrathecal; Intratracheal; Intravenous; Intravitreal; Subcutaneous; Vaginal Sodium Bisulfate Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Ophthalmic Sodium Bisulfite Infiltration (AN); Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Epidural; Inhalation; Intra-arterial; Intra-articular; Intrabursal; Intracardiac; Intradermal; Intradiscal; Intralesional; Intraperitoneal; Intrasynovial; Iontophoresis; Irrigation; Intravenous; Nerve Block; Ophthalmic; soft tissue; Topical Sodium Borate Auricular (Otic); Ophthalmic; Topical Sodium Borate Decahydrate Ophthalmic Sodium Carbonate Infiltration (AN); Intramuscular (IM); Infusion (IV); Intra-arterial; Intraperitoneal; Intrapleural; Intratumor; Intravascular; Intravenous; Intravitreal; Nerve Block; Ophthalmic; Rectal Sodium Carbonate Decahydrate Intravenous Sodium Carbonate Monohydrate Intra-arterial; Intracardiac; Intravenous; Ophthalmic Sodium Cetostearyl Sulfate Topical Sodium Chlorate Infiltration (AN); Intramuscular; Infusion (IV); Nerve Block Sodium Chloride Infiltration; Inhalation; Intra-arterial; Intra-articular; Intrabursal; Intracardiac; Intracaudal; Intracavitary; Intradermal; Intralesional; Intramuscular; Intraocular; Intraperitoneal; Intrapleural; Intrasynovial; Intrathecal; Intratracheal; Intratumor; Intravascular; Intravenous; Intravenous bolus; Intravesical; Intravitreal; Iontophoresis; Infusion (IV); Intramuscular (IM); Subcutaneous (SC); Nasal; Nerve Block; Ophthalmic; Parenteral; Peridural; Photopheresis; Rectal; Respiratory (Inhalation); Soft tissue; Subarachnoid; Submucosal; Topical; Transermal Sodium Chloride Injection Intramuscular Sodium Chloride Injection, Bacteriostatic Intraveous Sodium Cholesteryl Sulfate Infusion (IV) Sodium Citrate Infiltration (AN); Auricular (Otic); Epidural; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Inhalation; Intra-arterial; Intra-articular; Intracardiac; Intravacitary; Intralesional; Intraocular; Iintraperitoneal; Intrapleural; Intrasynovial; Intrathecal; Intratracheal; Intrauterine; Intravasular; Intravenous; Iontophoresis; Irrigation; Nasal; Nerve Block; Ophthalmic; Rectal; Respiratory (Inhalation); Soft tissue; Topical; Transdermal; Ureteral; Vaginal Sodium Cocoyl Sarcosinate Topical Sodium Desoxycholate Infusion (IV) Sodium Dithionite Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intravenous Sodium Dodecylbenzenesulfonate Topical Sodium Formaldehyde Sulfoxylate Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Topical Sodium Gluconate Intravenous; Infusion (IV) Sodium Hydroxide Intrathecal (AN, CNBLK); Infiltration (AN); Sympathetic (AN, NBLK); Auricular (Otic); Caudal Block; Dental; Epidural; Extracorporeal; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Infiltration; Inhalationi; Interstitial; Intra- amniotic; Intra-arterial; Intra-articular; Intrabursal; Intracardiac; Intracaudl; Intracavitary; Intradermal; Intradiscal; Intralesional; Intraocular; Intraperioneal; Intrapleural; Intraspinal; Intrasynovial; Intrathecal; Intratracheal; Intratumor; Intrauterine; Intravascular; Intravenous; Intravitreal; Iontophoresis; Irrigation; Nasal; Nerve Block; Ophthalmic; Parenteral; Perfusion, cardiac; Peridural; Perineural; Photopheresis; Rectal; Respiratory (Inhalation); Retrobular; Soft tissue; Spinal; Subarachnoid; Subconjunctival; Submucosal; Topical; Transdermal; Ureteral; Urethral; Vaginal Sodium Hypochlorite Infusion (IV) Sodium Iodide Intravenous; Topical Sodium Lactate Infiltration (AN); Caudal Black; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intracardiac; Intraperitoneal; Intravenous; Nerve Block; Topical Sodium Lactate, L- Epidural; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intracardiac; Nerve Block Sodium Laureth-2 Sulfate Topical Sodium Laureth-3 Sulfate Topical Sodium Laureth-5 Sulfate Topical Sodium Lauroyl Sarcosinate Topical Sodium Lauryl Sulfate Dental; Respiratory (Inhalation); Topical; Vaginal Sodium Lauryl Sulfoacetate Topical Sodium Metabisulfite Intrathecal (AN, CNBLK); Infiltration (AN); Cardal Block; Dental; Epidural; Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Infiltration; Inhalation; Intra-articular; Initrabursal; Intracardiac; Intramuscular; Intraperitoneal; Intravenous; Iontophoresis; Nerve Block; Ophthalmic; Peridural; Rectal; Submucosal; Topical; Vaginal Sodium Nitrate Ophthalmic Sodium Phosphate Intramuscular (IM); Infusion (IV); Intra-articular; Intrabursal; Intradermal; Intralesional; Nasal; Nerve Block; Ophthalmic; Soft tissue; Subcutanesou; Topical Sodium Phosphate Dihydrate Intramuscular (IM); Subcutaneous (SC); Ophthalmic Sodium Phosphate, Dibasic Intramuscular (IM); Infusion (IV); Intradermal; Intralesional; Intrasynovial; Intravenous; Nasal; Ophthalmic; Soft tissue; Topical; Subcutaneous (SC) Sodium Phosphate, Dibasic, Anhydrous Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intra-articular; Intralesional; Intramuscular; Intravenous; Intravesical; Nasal; Ophthalmic; Topical; Vaginal Sodium Phosphate, Dibasic, Dihydrate Intramuscular (IM); Infusion (IV); Intravenous; Nasal; Ophthalmic; Subcutaneous; Topical Sodium Phosphate, Dibasic, Dodecahydrate Nasal Sodium Phosphate, Dibasic, Heptahydrate Infiltration (AN); Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Iintra- articular; Intrabursal; Intradermal; Intralesional; Intramuscular; Intrasynovial; Intravenous; Intravitreal; Nasal; Nerve Block; Ophthalmic; Soft tissue; Topical; Urethral Sodium Phosphate, Monobasic Intramuscular (IM); Infusion (IV); Intralesional; Intrasynovial; Iontophoresis; Ophthalmic; Soft tissue; Subcutaneous; Topical Sodium Phosphate, Monobasic, Anhydrous Auricular (Otic); Intramuscular (IM); Infusion (IV); Intrabursal; Intradermal; Intralesional; Intrasynovial; Intravascular; Intravenous; Intravesical; Nasal; Ophthalmic; Soft tissue; Subcutaneous; Topical; Vaginal Sodium Phosphate, Monobasic, Dihydrate Intravenous; Infusion (IV); Nasal; Ophthalmic; Subcutaneous; Topical Sodium Phosphate, Monobasic, Intramuscular (IM); Infusion (IV); Intra-articular; Monohydrate Intralesional; Intravascular; Intravenous; Intravitreal; Ophthalmic; Subcutaneous; Topical Sodium Polyacrylate (2500000 Mw) Topical Sodium Pyrophosphate Intravenous Sodium Pyrrolidone Carboxylate Topical Sodium Starch Glycolate Transmucosal Sodium Succinate Hexahydrate Intravenous Sodium Sulfate Intramuscular (IM); Infusion (IV); Ophthalmic Sodium Sulfate Anhydrous Inhalation; Iintramuscular; Ophthalmic Sodium Sulfate Decahydrate Ophthalmic Sodium Sulfite Auricular (Otic); Epidural; Intramuscular (IM); Infusion (IV); Inhalation; Intra-articular; Intralesional; Intravenous; Ophthalmic; Soft tissue; Subcutaneous; Topical Sodium Sulfosuccinated Undecyclenic Topical Monoalkylolamide Sodium Tartrate Intramuscual (IM); Infusion (IV); Intravenous Sodium Thioglycolate Subcutaneous Sodium Thiomalate Intramuscular (IM); Infusion (IV) Sodium Thiosulfate Intravenous; Ophthalmic; Topical Sodium Thiosulfate Anhydrous Intravenous Sodium Trimetaphosphate Intravenous Sodium Xylenesulfonate Topical Somay 44 Topical Sorbic Acid Ophthalmic; Topical; Vaginal Sorbitan Topical Sorbitan Isostearate Topical Sorbitan Monolaurate Ophthalmic; Topical Sorbitan Monooleate Rectal; Topical; Transdermal Sorbitan Monopalmitate Intramuscular; Topical Sorbitan Monostearate Topical; Vaginal Sorbitan Sesquioleate Rectal; Topical Sorbitan Trioleate Inhalation; Nasal Sorbitan Tristearate Topical Sorbitol Dental; Intra-articular; Intralesional; Intramuscular; Intrasynovial; Intravenous; Infusion (IV); Nasal; Ophthalmic; Rectal; Topical; Vaginal Sorbitol Solution Intra-articular; Intralesional; Intramuscular; Intravenous; Infusion (IV); Nasal; Ophthalmic; Rectal; Topical; Vaginal Soybean Flour Topical Soybean Oil Intraveous; Infusion (IV); Topical Spearmint Oil Topical Spermaceti Topical; Vaginal Squalane Topical Stabilized Oxychloro Complex Ophthalmic Stannous 2-Ethylhexanoate Vagianl Stannous Chloride Intravenous; Infusion (IV) Stannous Chloride Anhydrous Intravenous; Infusion (IV) Stannous Fluoride Intravenous Stannous Tartrate Intravenous Starch Intramuscular; Rectal; Topical; Vaginal Starch 1500, Pregelatinized Vagianl Starch, Corn Vagianl Stearalkonium Chloride Topical Stearalkonium Hectorite/Propylene Transdermal Carbonate Stearamidoethyl Diethylamine Topical; Vaginal Steareth-10 Rectal; Topical Steareth-100 Topical Steareth-2 Topical Steareth-20 Topical Steareth-21 Topical Steareth-40 Topical; Rectal Stearic Acid Implantation; Subcutaneous; Topical; Vaginal Stearic Diethanolamide Topical Stearoxytrimethylsilane Topical Steartrimonium Hydrolyzed Animal Topical Collagen Stearyl Alcohol Topical; Vaginal Sterile Water For Inhalation Infusion (IV) Styrene/Isoprene/Styrene Block Copolymer Topical Succimer Intravenous Succinic Acid Intramuscular (IM); Infusion (IV); Intravenous Sucralose Nasa Sucrose Intramuscular; Intravenous; Infusion (IV); Rectal; Subcutaneous; Topical Sucrose Distearate Topical Sucrose Polyesters Topical Sulfacetamide Sodium Topical Sulfobutylether .Beta.-Cyclodextrin Intramuscular; Intravenous; Infusion (IV) Sulfur Dioxide Infusion (IV) Sulfuric Acid Auricular (Otic); Epidural; Intramuscular (IM); Infusion (IV); Inhalation; Intraperitoneal; Intravenous; Irrigation; Nasal; Ophthalmic; Respiratory (Inhalation); Topical Sulfurous Acid Intramuscular Surfactol Qs Topical Tagatose, D- Rectal Talc Topical Tall Oil Topical Tallow Glycerides Topical Tartaric Acid Intramuscular; Intravenous; Infusion (IV); Topical Tartaric Acid, Dl- Intramuscular (IM); Infusion (IV); Intravenous; Rectal; Vaginal Tenox Topical Tenox-2 Topical Tert-Butyl Alcohol Intravenous; Infusion (IV); Topical Tert-Butyl Hydroperoxide Topical Tert-Butylhydroquinone Vagianl Tetrakis(2- Intravenous Methoxyisobutylisocyanide)Copper(I) Tetrafluoroborate Tetrapropyl Orthosilicate Vagianl Tetrofosmin Infusion (IV) Theophylline Intravenous; Infusion (IV) Thimerosal Auricular (Otic); Intramuscular (IM); Infusion (IV); Subcutaneous (SC); Intravenous; Ophthalmic; Topical Threonine Intravenous; Infusion (IV) Thymol Inhalation Tin Intravenous Titanium Dioxide Dental; Intrauterine; Ophthalmic; Respiratory (Inhalation); Topical; Transdermal Tocopherol Topical Tocophersolan Ophthalmic; Topical Triacetin Endocervical; Transdermal Tricaprylin Epidural; Infiltration Trichloromonofluoromethane Inhalation; Nasal; Topical Trideceth-10 Topical Triethanolamine Lauryl Sulfate Topical Trifluoroacetic Acid Infusion (IV) Triglycerides, Medium Chain Topical Trihydroxystearin Topical Trilaneth-4 Phosphate Topical Trilaureth-4 Phosphate Topical Trisodium Citrate Dihydrate Intramuscular (IM); Infusion (IV); Intravenous; Intravitreal; Nasal; Ophthalmic; Topical Trisodium Hedta Topical Triton 720 Ophthalmic Triton X-200 Topical Trolamine Rectal; Topical; Transdermal; Vaginal Tromantadine Intramuscular; Intravenous Tromethamine Intramuscular (IM); Infusion (IV); Intra-arterial; Intrathecal; Intratracheal; Intravasular; Intravenous; Ophthalmic; Rectal; Respiratory (Inhalation); Subcutaneous; Topical; Transdermal; Urethral Tryptophan Infusion (IV) Tyloxapol Ophthalmic; Topical Tyrosine Infusion (IV) Undecylenic Acid Topical Union 76 Amsco-Res 6038 Transdermal Urea Intramuscular; Vaginal Valine Infusion (IV) Vegetable Oil Topical Vegetable Oil Glyceride, Hydrogenated Rectal Vegetable Oil, Hydrogenated Rectal; Topical; Vaginal Versetamide Intravenous Viscarin Topical Viscose/Cotton Transdermal Vitamin E Topical Wax, Emulsifying Rectal; Topical Wecobee Fs Topical; Vaginal White Ceresin Wax Vagianl White Wax Rectal; Topical; Vaginal Xanthan Gum Rectal; Topical Zinc Subcutaneous Zinc Acetate Subcutaneous, Topical Zinc Carbonate Subcutaneous Zinc Chloride Intramuscular (IM); Subcutaneous (SC); Intradermal; Ophthalmic Zinc Oxide Intramuscular (IM); Subcutaneous (SC); Rectal; Respiratory (Inhalation) Delivery

The present disclosure encompasses the delivery of NAVs for any of therapeutic, pharmaceutical, diagnostic or imaging by any appropriate route taking into consideration likely advances in the sciences of drug delivery. Delivery may be naked or formulated.

Naked Delivery

The NAVs of the present invention may be delivered to a cell naked. As used herein in, “naked” refers to delivering NAVs free from agents which promote transfection. For example, the NAVs delivered to the cell may contain no modifications. The naked NAVs may be delivered to the cell using routes of administration known in the art and described herein.

Formulated Delivery

The NAVs of the present invention may be formulated, using the methods described herein. The formulations may contain polynucleotides which may be modified and/or unmodified. The formulations may further include, but are not limited to, cell penetration agents, a pharmaceutically acceptable carrier, a delivery agent, a bioerodible or biocompatible polymer, a solvent, and a sustained-release delivery depot. The formulated NAVs may be delivered to the cell using routes of administration known in the art and described herein.

The compositions may also be formulated for direct delivery to an organ or tissue in any of several ways in the art including, but not limited to, direct soaking or bathing, via a catheter, by gels, powder, ointments, creams, gels, lotions, and/or drops, by using substrates such as fabric or biodegradable materials coated or impregnated with the compositions, and the like.

Administration

The NAVs of the present invention may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited to enteral (into the intestine), gastroenteral, epidural (into the dura matter), oral (by way of the mouth), transdermal, peridural, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intravenous bolus, intravenous drip, intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), in ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial, endotracheal, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intrabursal, intracartilaginous (within a cartilage), intracaudal (within the cauda equine), intracisternal (within the cisterna magna cerebellomedularis), intracorneal (within the cornea), dental intracornal, intracoronary (within the coronary arteries), intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradiscal (within a disc), intraductal (within a duct of a gland), intraduodenal (within the duodenum), intradural (within or beneath the dura), intraepidermal (to the epidermis), intraesophageal (to the esophagus), intragastric (within the stomach), intragingival (within the gingivae), intraileal (within the distal portion of the small intestine), intralesional (within or introduced directly to a localized lesion), intraluminal (within a lumen of a tube), intralymphatic (within the lymph), intramedullary (within the marrow cavity of a bone), intrameningeal (within the meninges), intraocular (within the eye), intraovarian (within the ovary), intrapericardial (within the pericardium), intrapleural (within the pleura), intraprostatic (within the prostate gland), intrapulmonary (within the lungs or its bronchi), intrasinal (within the nasal or periorbital sinuses), intraspinal (within the vertebral column), intrasynovial (within the synovial cavity of a joint), intratendinous (within a tendon), intratesticular (within the testicle), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrathoracic (within the thorax), intratubular (within the tubules of an organ), intratumor (within a tumor), intratympanic (within the aurus media), intravascular (within a vessel or vessels), intraventricular (within a ventricle), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), irrigation (to bathe or flush open wounds or body cavities), laryngeal (directly upon the larynx), nasogastric (through the nose and into the stomach), occlusive dressing technique, ophthalmic (to the external eye), oropharyngeal (directly to the mouth and pharynx), parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), retrobulbar (behind the pons or behind the eyeball), intramyocardial (entering the myocardium), soft tissue, subarachnoid, subconjunctival, submucosal, transplacental (through or across the placenta), transtracheal (through the wall of the trachea), transtympanic (across or through the tympanic cavity), ureteral (to the ureter), urethral (to the urethra), vaginal, caudal block, diagnostic, nerve block, biliary perfusion, cardiac perfusion, photopheresis or spinal. In specific embodiments, compositions may be administered in a way which allows them cross the blood-brain barrier, vascular barrier, or other epithelial barrier. In one embodiment, a formulation for a route of administration may include at least one inactive ingredient. Non-limiting examples of routes of administration and inactive ingredients which may be included in formulations for the specific route of administration is shown in Table 20. In Table 27, “AN” means anesthetic, “CNBLK” means cervical nerve block, “NBLK” means nerve block, “IV” means intravenous, “TM” means intramuscular and “SC” means subcutaneous.

TABLE 27 Routes of Adminsitration and Inactive Ingredients Route of Administration Inactive Ingredient Intrathecal (AN, CNBLK) Acetone Sodium Bisulfite; Citric Acid; Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide; Sodium Metabisulfite Infiltration (AN) Acetic Acid; Acetone Sodium Bisulfite; Ascorbic Acid; Benzyl Alcohol; Calcium Chloride; Carbon Dioxide; Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Hydrochloric Acid, Diluted; Lactic Acid; Methylparaben; Monothioglycerol; Nitrogen; Potassium Chloride; Potassium Metabisulfite; Potassium Phosphate, Monobasic; Propylparaben; Sodium Bisulfite; Sodium Carbonate; Sodium Chlorate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate; Sodium Metabisulfite; Sodium Phosphate, Dibasic, Heptahydrate Sympathetic NBLK (AN) Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide Auricular (Otic) Acetic Acid; Aluminum Acetate; Aluminum Sulfate Anhydrous; Benzalkonium Chloride; Benzethonium Chloride; Benzyl Alcohol; Boric Acid; Calcium Carbonate; Cetyl Alcohol; Chlorobutanol; Chloroxylenol; Citric Acid; Creatinine; Cupric Sulfate; Cupric Sulfate Anhydrous; Edetate Disodium; Edetic Acid; Glycerin; Glyceryl Stearate; Hydrochloric Acid; Hydrocortisone; Hydroxyethyl Cellulose; Isopropyl Myristate; Lactic Acid; Lecithin, Hydrogenated; Methylparaben; Mineral Oil; Petrolatum; Petrolatum, White; Phenylethyl Alcohol; Polyoxyl 40 Stearate; Polyoxyl Stearate; Polysorbate 20; Polysorbate 80; Polyvinyl Alcohol; Potassium Metabisulfite; Potassium Phosphate, Monobasic; Povidone K90f; Povidones; Propylene Glycol; Propylene Glycol Diacetate; Propylparaben; Sodium Acetate; Sodium Bisulfite; Sodium Borate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous; Sodium Sulfite; Sulfuric Acid; Thimerosal Caudal Block Ascorbic Acid; Calcium Chloride; Citric Acid; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Methylparaben; Monothioglycerol; Nitrogen; Potassium Chloride; Sodium Chloride; Sodium Hydroxide; Sodium Lactate; Sodium Metabisulfite Dental Acetone Sodium Bisulfite; Alcohol; Alcohol, Dehydrated; Alcohol, Denatured; Anethole; Benzyl Alcohol; Carboxymethylcellulose Sodium; Carrageenan; D&C Yellow No. 10; Dimethicone Medical Fluid 360; Eucalyptol; Fd&C Blue No. 1; Fd&C Green No. 3; Flavor 89-186; Flavor 89-259; Flavor Df-119; Flavor Df-1530; Flavor Enhancer; Gelatin; Gelatin, Crosslinked; Glycerin; Glyceryl Stearate; High Density Polyethylene; Hydrocarbon Gel, Plasticized; Hydrochloric Acid; Menthol; Mineral Oil; Nitrogen; Pectin; Peg-40 Sorbitan Diisostearate; Peppermint Oil; Petrolatum, White; Plastibase-50w; Polyethylene Glycol 1540; Polyglactin; Polyols; Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Propylene Glycol; Pvm/Ma Copolymer; Saccharin Sodium; Silica, Dental; Silicon Dioxide; Sodium Benzoate; Sodium Chloride; Sodium Hydroxide; Sodium Lauryl Sulfate; Sodium Metabisulfite; Sorbitol; Titanium Dioxide Diagnostic Hydrochloric Acid Endocervical Colloidal Silicon Dioxide; Triacetin Epidural 1,2-Dioleoyl-Sn-Glycero-3-Phosphocholine; 1,2-Dipalmitoyl-Sn- Glycero-3-(Phospho-Rac-(1-Glycerol)); Ascorbic Acid; Benzyl Alcohol; Calcium Chloride; Cholesterol; Citric Acid; Edetate Calcium Disodium; Edetate Disodium; Glyceryl Trioleate; Hydrochloric Acid; Isotonic Sodium Chloride Solution; Methylparaben; Monothioglycerol; Nitrogen; Potassium Chloride; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate, L-; Sodium Metabisulfite; Sodium Sulfite; Sulfuric Acid; Tricaprylin Extracorporeal Acetic Acid; Alcohol, Dehydrated; Benzyl Alcohol; Hydrochloric Acid; Propylene Glycol; Sodium Acetate; Sodium Chloride; Sodium Hydroxide Intramuscular-Intravenous Acetic Acid; Alcohol; Alcohol, Dehydrated; Alcohol, Diluted; Anhydrous Dextrose; Anhydrous Lactose; Anhydrous Trisodium Citrate; Arginine; Ascorbic Acid; Benzethonium Chloride; Benzoic Acid; Benzyl Alcohol; Calcium Chloride; Carbon Dioxide; Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Creatinine; Dextrose; Edetate Calcium Disodium; Edetate Disodium; Edetate Sodium; Gluconolactone; Glycerin; Hydrochloric Acid; Hydrochloric Acid, Diluted; Lactic Acid; Lactic Acid, Dl-; Lactose; Lactose Monohydrate; Lactose, Hydrous; Lysine; Mannitol; Methylparaben; Monothioglycerol; Niacinamide; Nitrogen; Phenol; Phenol, Liquefied; Phosphoric Acid; Polyethylene Glycol 300; Polyethylene Glycol 400; Polypropylene Glycol; Polysorbate 40; Potassium Metabisulfite; Potassium Phosphate, Monobasic; Propylene Glycol; Propylparaben; Saccharin Sodium; Saccharin Sodium Anhydrous; Silicone; Simethicone; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfate; Sodium Bisulfite; Sodium Carbonate; Sodium Chloride; Sodium Citrate; Sodium Formaldehyde Sulfoxylate; Sodium Hydroxide; Sodium Lactate, L-; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfate; Sodium Sulfite; Sodium Tartrate; Sodium Thiomalate; Succinic Acid; Sulfuric Acid; Tartaric Acid, Dl-; Thimerosal; Trisodium Citrate Dihydrate; Tromethamine Intramuscular-Intravenous- Acetic Acid; Alcohol; Alcohol, Dehydrated; Benzyl Alcohol; Subcutaneous Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Citric Acid, Hydrous; Creatinine; Dextrose; Edetate Disodium; Edetate Sodium; Gelatin; Glycerin; Glycine; Hydrochloric Acid; Hydrochloric Acid, Diluted; Lactic Acid; Lactose; Lactose Monohydrate; Metacresol; Methanesulfonic Acid; Methylparaben; Monothioglycerol; Nitrogen; Phenol; Phosphoric Acid; Polyoxyethylene Fatty Acid Esters; Propylparaben; Sodium Acetate; Sodium Bisulfate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Dithionite; Sodium Hydroxide; Sodium Lactate; Sodium Lactate, L-; Sodium Metabisulfite; Sodium Phosphate, Dibasic, Heptahydrate; Thimerosal Intramuscular - Acetic Acid; Anhydrous Dextrose; Benzyl Alcohol; Chlorobutanol; Subcutaneous Citric Acid; Cysteine; Edetate Disodium; Gelatin; Glycerin; Glycine; Hydrochloric Acid; Lactose Monohydrate; Mannitol; Metacresol; Methylparaben; Nitrogen; Peg Vegetable Oil; Peg-40 Castor Oil; Phenol; Phenol, Liquefied; Phosphoric Acid; Polyoxyethylene Fatty Acid Esters; Polysorbate 20; Propylparaben; Protamine Sulfate; Sesame Oil; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Chloride; Sodium Citrate; Sodium Formaldehyde Sulfoxylate; Sodium Hydroxide; Sodium Phosphate Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sulfuric Acid; Thimerosal; Zinc Chloride; Zinc Oxide Implantation Acetone; Crospovidone; Dimethylsiloxane/Methylvinylsiloxane Copolymer; Ethylene Vinyl Acetate Copolymer; Magnesium Stearate; Poly(Bis(P-Carboxyphenoxy)Propane Anhydride): Sebacic Acid; Polyglactin; Silastic Brand Medical Grade Tubing; Silastic Medical Adhesive, Silicone Type A; Stearic Acid Infiltration Cholesterol; Citric Acid; Diethyl Pyrocarbonate; Dipalmitoylphosphatidylglycerol, Dl-; Hydrochloric Acid; Nitrogen; Phosphoric Acid; Sodium Chloride; Sodium Hydroxide; Sodium Metabisulfite; Tricaprylin Inhalation Acetone Sodium Bisulfite; Acetylcysteine; Alcohol; Alcohol, Dehydrated; Ammonia; Ascorbic Acid; Benzalkonium Chloride; Carbon Dioxide; Cetylpyridinium Chloride; Chlorobutanol; Citric Acid; D&C Yellow No. 10; Dichlorodifluoromethane; Dichlorotetrafluoroethane; Edetate Disodium; Edetate Sodium; Fd&C Yellow No. 6; Fluorochlorohydrocarbons; Glycerin; Hydrochloric Acid; Hydrochloric Acid, Diluted; Lactose; Lecithin; Lecithin, Hydrogenated Soy; Lecithin, Soybean; Menthol; Methylparaben; Nitric Acid; Nitrogen; Norflurane; Oleic Acid; Propylene Glycol; Propylparaben; Saccharin; Saccharin Sodium; Sodium Bisulfate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sodium Sulfate Anhydrous; Sodium Sulfite; Sorbitan Trioleate; Sulfuric Acid; Thymol; Trichloromonofluoromethane Interstitial Benzyl Alcohol; Dextrose; Hydrochloric Acid; Sodium Acetate; Sodium Hydroxide Intra-amniotic Citric Acid; Edetate Disodium Anhydrous; Hydrochloric Acid; Sodium Hydroxide Intra-arterial Anhydrous Trisodium Citrate; Benzyl Alcohol; Carbon Dioxide; Citric Acid; Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Hydrochloric Acid, Diluted; Iodine; Meglumine; Methylparaben; Nitrogen; Propylparaben; Sodium Bisulfite; Sodium Carbonate; Sodium Carbonate Monohydrate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Tromethamine Intra-articular Acetic Acid; Anhydrous Trisodium Citrate; Benzalkonium Chloride; Benzyl Alcohol; Carboxymethylcellulose; Carboxymethylcellulose Sodium; Cellulose, Microcrystalline; Citric Acid; Creatine; Creatinine; Crospovidone; Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium; Hyaluronate Sodium; Hydrochloric Acid; Iodine; Meglumine; Methylcelluloses; Methylparaben; Myristyl-.Gamma.-Picolinium Chloride; Niacinamide; Phenol; Phosphoric Acid; Polyethylene Glycol 3350; Polyethylene Glycol 4000; Polysorbate 80; Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic; Propylparaben; Sodium Acetate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfite; Sorbitol; Sorbitol Solution Intrabursal Anhydrous Trisodium Citrate; Benzalkonium Chloride; Benzyl Alcohol; Carboxymethylcellulose; Carboxymethylcellulose Sodium; Citric Acid; Creatinine; Edetate Disodium; Hydrochloric Acid; Methylparaben; Polysorbate 80; Propylparaben; Sodium Bisulfite; Sodium Chloride; Sodium Hydroxide; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous Intracardiac Carbon Dioxide; Citric Acid; Citric Acid Monohydrate; Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Iodine; Lactic Acid; Meglumine; Sodium Bisulfite; Sodium Carbonate Monohydrate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate; Sodium Lactate, L-; Sodium Metabisulfite Intracaudal Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide Intracavitary Alcohol, Dehydrated; Alfadex; Anhydrous Lactose; Benzyl Alcohol; Dextrose; Hydrochloric Acid; Lactose; Lactose Monohydrate; Nitrogen; Sodium Acetate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide Intradermal Benzalkonium Chloride; Benzyl Alcohol; Carboxymethylcellulose Sodium; Creatinine; Edetate Disodium; Glycerin; Hydrochloric Acid; Metacresol; Methylparaben; Phenol; Polysorbate 80; Protamine Sulfate; Sodium Acetate; Sodium Bisulfite; Sodium Chloride; Sodium Hydroxide; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous; Zinc Chloride Intradiscal Cysteine Hydrochloride Anhydrous; Cysteine, Dl-; Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium; Iodine; Meglumine; Sodium Bisulfite; Sodium Hydroxide Intralesional Acetic Acid; Benzalkonium Chloride; Benzyl Alcohol; Carboxymethylcellulose; Carboxymethylcellulose Sodium; Citric Acid; Creatine; Creatinine; Edetate Disodium; Hydrochloric Acid; Methylcelluloses; Methylparaben; Myristyl-.Gamma.-Picolinium Chloride; Niacinamide; Phenol; Phosphoric Acid; Polyethylene Glycol 3350; Polyethylene Glycol 4000; Polysorbate 80; Propylparaben; Sodium Acetate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfite; Sorbitol; Sorbitol Solution Intralymphatic Poppy Seed Oil Intramuscular Acetic Acid; Activated Charcoal; Adipic Acid; Alcohol; Alcohol, Dehydrated; Ammonium Acetate; Anhydrous Dextrose; Ascorbic Acid; Benzalkonium Chloride; Benzethonium Chloride; Benzoic Acid; Benzyl Alcohol; Benzyl Benzoate; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylparaben; Calcium; Calcium Chloride; Carbon Dioxide; Carboxymethylcellulose; Carboxymethylcellulose Sodium; Castor Oil; Cellulose, Microcrystalline; Chlorobutanol; Chlorobutanol Hemihydrate; Chlorobutanol, Anhydrous; Citric Acid; Citric Acid Monohydrate; Corn Oil; Cottonseed Oil; Creatine; Creatinine; Croscarmellose Sodium; Crospovidone; Dextrose; Diatrizoic Acid; Docusate Sodium; Edetate Calcium Disodium; Edetate Disodium; Edetate Disodium Anhydrous; Edetate Sodium; Ethyl Acetate; Gelatin; Glutathione; Glycerin; Glycine; Hyaluronate Sodium; Hydrochloric Acid; Hydroxide Ion; Lactic Acid; Lactic Acid, Dl-; Lactose; Lactose Monohydrate; Lactose, Hydrous; Lecithin; Magnesium Chloride; Maleic Acid; Mannitol; Meglumine; Metacresol; Methionine; Methylcelluloses; Methylparaben; Monothioglycerol; Myristyl-.Gamma.-Picolinium Chloride; N,N-Dimethylacetamide; Niacinamide; Nitrogen; Peanut Oil; Peg-20 Sorbitan Isostearate; Phenol; Phenylmercuric Nitrate; Phosphoric Acid; Polyethylene Glycol 200; Polyethylene Glycol 300; Polyethylene Glycol 3350; Polyethylene Glycol 4000; Polyglactin; Polylactide; Polysorbate 20; Polysorbate 40; Polysorbate 80; Polyvinyl Alcohol; Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic; Povidones; Propyl Gallate; Propylene Glycol; Propylparaben; Saccharin Sodium; Saccharin Sodium Anhydrous; Sesame Oil; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfite; Sodium Carbonate; Sodium Chlorate; Sodium Chloride; Sodium Chloride Injection; Sodium Citrate; Sodium Formaldehyde Sulfoxylate; Sodium Hydroxide; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfate Anhydrous; Sodium Sulfite; Sodium Tartrate; Sorbitan Monopalmitate; Sorbitol; Sorbitol Solution; Starch; Sucrose; Sulfobutylether .Beta.- Cyclodextrin; Sulfuric Acid; Sulfurous Acid; Tartaric Acid; Thimerosal; Tromantadine; Tromethamine; Urea Intraocular Benzalkonium Chloride; Calcium Chloride; Citric Acid Monohydrate; Hydrochloric Acid; Magnesium Chloride; Polyvinyl Alcohol; Potassium Chloride; Sodium Acetate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide Intraperitoneal Benzyl Alcohol; Calcium Chloride; Dextrose; Edetate Calcium Disodium; Hydrochloric Acid; Magnesium Chloride; Sodium Acetate; Sodium Bicarbonate; Sodium Bisulfite; Sodium Carbonate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate; Sodium Metabisulfite; Sulfuric Acid Intrapleural Benzyl Alcohol; Citric Acid; Dextrose; Dichlorodifluoromethane; Hydrochloric Acid; Sodium Acetate; Sodium Carbonate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide Intraspinal Dextrose; Hydrochloric Acid; Sodium Hydroxide Intrasynovial Acetic Acid; Benzyl Alcohol; Carboxymethylcellulose Sodium; Citric Acid; Creatinine; Edetate Disodium; Hydrochloric Acid; Methylcelluloses; Methylparaben; Myristyl-.Gamma.-Picolinium Chloride; Niacinamide; Phenol; Polyethylene Glycol 3350; Polyethylene Glycol 4000; Polysorbate 80; Propylparaben; Sodium Acetate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sorbitol Intrathecal Benzyl Alcohol; Carbon Dioxide; Citric Acid; Edetate Calcium Disodium; Hydrochloric Acid; Methionine; Nitrogen; Pentetate Calcium Trisodium; Pentetic Acid; Sodium Bicarbonate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sulfuric Acid; Tromethamine Intratracheal Acetic Acid; Benzyl Alcohol; Carboxymethylcellulose Sodium; Hydrochloric Acid; Isotonic Sodium Chloride Solution; Peanut Oil; Sodium Bicarbonate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Tromethamine Intratumor Benzyl Alcohol; Hydrochloric Acid; Nitrogen; Sodium Carbonate; Sodium Chloride; Sodium Hydroxide Intrauterine Barium Sulfate; Crospovidone; Diatrizoic Acid; Dimethylsiloxane/Methylvinylsiloxane Copolymer; Edetate Calcium Disodium; Edetate Disodium; Ethylene Vinyl Acetate Copolymer; High Density Polyethylene; Meglumine; Polyethylene High Density Containing Ferric Oxide Black (<1%); Polyethylene Low Density Containing Barium Sulfate (20-24%); Polyethylene T; Polypropylene; Poppy Seed Oil; Potassium Phosphate, Monobasic; Silicone; Sodium Citrate; Sodium Hydroxide; Titanium Dioxide Intravascular Alcohol; Alcohol, Dehydrated; Calcium Chloride; Carbon Dioxide; Citric Acid; Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Hydrochloric Acid, Diluted; Iodine; Meglumine; Nitrogen; Potassium Hydroxide; Sodium Carbonate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Monohydrate; Tromethamine Intravenous Alpha-Tocopherol; Alpha-Tocopherol, Dl-; 1,2-Dimyristoyl-Sn-Glycero- 3-Phosphocholine; 1,2-Distearoyl-Sn-Glycero-3-(Phospho-Rac-(1- Glycerol)); 1,2-Distearoyl-Sn-Glycero-3-Phosphocholine; Acetic Acid; Acetic Acid, Glacial; Acetic Anhydride; Acetylated Monoglycerides; Acetyltryptophan, Dl-; Activated Charcoal; Albumin Aggregated; Albumin Colloidal; Albumin Human; Alcohol; Alcohol, Dehydrated; Alcohol, Denatured; Ammonium Acetate; Ammonium Hydroxide; Ammonium Sulfate; Anhydrous Citric Acid; Anhydrous Dextrose; Anhydrous Lactose; Anhydrous Trisodium Citrate; Arginine; Ascorbic Acid; Benzenesulfonic Acid; Benzethonium Chloride; Benzoic Acid; Benzyl Alcohol; Benzyl Chloride; Bibapcitide; Boric Acid; Butylated Hydroxytoluene; Calcium Chloride; Calcium Gluceptate; Calcium Hydroxide; Calcobutrol; Caldiamide Sodium; Caloxetate Trisodium; Calteridol Calcium; Captisol; Carbon Dioxide; Cellulose, Microcrystalline; Chlorobutanol; Chlorobutanol Hemihydrate; Chlorobutanol, Anhydrous; Cholesterol; Citrate; Citric Acid; Citric Acid Monohydrate; Citric Acid, Hydrous; Cysteine; Cysteine Hydrochloride; Dalfampridine; Dextran; Dextran 40; Dextrose; Dextrose Monohydrate; Dextrose Solution; Diatrizoic Acid; Dimethicone Medical Fluid 360; Edetate Calcium Disodium; Edetate Disodium; Edetate Disodium Anhydrous; Egg Phospholipids; Ethanolamine Hydrochloride; Ethylenediamine; Exametazime; Ferric Chloride; Gadolinium Oxide; Gamma Cyclodextrin; Gelatin; Gentisic Acid; Gluceptate Sodium; Gluceptate Sodium Dihydrate; Gluconolactone; Glucuronic Acid; Glycerin; Glycine; Guanidine Hydrochloride; Hetastarch; Histidine; Human Albumin Microspheres; Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydroxyethylpiperazine Ethane Sulfonic Acid; Hydroxypropyl- Bcyclodextrin; Iodine; Iodoxamic Acid; Iofetamine Hydrochloride; Isopropyl Alcohol; Isotonic Sodium Chloride Solution; Lactic Acid; Lactic Acid, Dl-; Lactic Acid, L-; Lactobionic Acid; Lactose; Lactose Monohydrate; Lactose, Hydrous; Lecithin, Egg; Lecithin, Hydrogenated Soy; Lidofenin; Mannitol; Mebrofenin; Medronate Disodium; Medronic Acid; Meglumine; Methionine; Methylboronic Acid; Methylene Blue; Methylparaben; Monothioglycerol; N-(Carbamoyl-Methoxy Peg-40)-1,2- Distearoyl-Cephalin Sodium; N,N-Dimethylacetamide; Nioxime; Nitrogen; Octanoic Acid; Oxidronate Disodium; Oxyquinoline; Pentasodium Pentetate; Pentetate Calcium Trisodium; Pentetic Acid; Perflutren; Phenol; Phenol, Liquefied; Phosphatidyl Glycerol, Egg; Phospholipid, Egg; Phosphoric Acid; Poloxamer 188; Polyethylene Glycol 300; Polyethylene Glycol 400; Polyethylene Glycol 600; Polysiloxane; Polysorbate 20; Polysorbate 80; Potassium Bisulfite; Potassium Chloride; Potassium Hydroxide; Potassium Metabisulfite; Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic; Povidones; Propylene Glycol; Propylparaben; Saccharin Sodium; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Ascorbate; Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfite; Sodium Carbonate; Sodium Carbonate Decahydrate; Sodium Carbonate Monohydrate; Sodium Chloride; Sodium Chloride Injection, Bacteriostatic; Sodium Citrate; Sodium Dithionite; Sodium Gluconate; Sodium Hydroxide; Sodium Iodide; Sodium Lactate; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate; Sodium Pyrophosphate; Sodium Succinate Hexahydrate; Sodium Sulfite; Sodium Tartrate; Sodium Thiosulfate; Sodium Thiosulfate Anhydrous; Sodium Trimetaphosphate; Sorbitol; Sorbitol Solution; Soybean Oil; Stannous Chloride; Stannous Chloride Anhydrous; Stannous Fluoride; Stannous Tartrate; Succimer; Succinic Acid; Sucrose; Sulfobutylether .Beta.- Cyclodextrin; Sulfuric Acid; Tartaric Acid; Tartaric Acid, Dl-; Tert-Butyl Alcohol; Tetrakis(2-Methoxyisobutylisocyanide)Copper(I) Tetrafluoroborate; Theophylline; Thimerosal; Threonine; Tin; Trisodium Citrate Dihydrate; Tromantadine; Tromethamine; Versetamide Intravenous Bolus Sodium Chloride Intravesical Alcohol, Dehydrated; Edetate Calcium Disodium; Hydrochloric Acid; Nitrogen; Polyoxyl 35 Castor Oil; Potassium Phosphate, Monobasic; Sodium Chloride; Sodium Hydroxide; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Monobasic, Anhydrous Intravitreal Calcium Chloride; Carboxymethylcellulose Sodium; Cellulose, Microcrystalline; Hyaluronate Sodium; Hydrochloric Acid; Magnesium Chloride; Magnesium Stearate; Polysorbate 80; Polyvinyl Alcohol; Potassium Chloride; Sodium Acetate; Sodium Bicarbonate; Sodium Carbonate; Sodium Chloride; Sodium Hydroxide; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Monohydrate; Trisodium Citrate Dihydrate Iontophoresis Cetylpyridinium Chloride; Citric Acid; Edetate Disodium; Glycerin; Hydrochloric Acid; Methylparaben; Phenonip; Polacrilin; Polyvinyl Alcohol; Povidone Hydrogel; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sodium Phosphate, Monobasic Irrigation Acetic Acid; Activated Charcoal; Benzoic Acid; Hydrochloric Acid; Hypromelloses; Methylparaben; Nitrogen; Sodium Bisulfite; Sodium Citrate; Sodium Hydroxide; Sulfuric Acid Intravenous - Acetic Acid; Alcohol; Benzyl Alcohol; Calcium Hydroxide; Subcutaneous Chlorobutanol; Glycerin; Hydrochloric Acid; Lactose Monohydrate; Methylparaben; Nitrogen; Phenol; Phenol, Liquefied; Phosphoric Acid; Propylparaben; Sodium Acetate; Sodium Carbonate; Sodium Chloride; Sodium Hydroxide Intravenous (Infusion) 1,2-Dimyristoyl-Sn-Glycero-3-(Phospho-S-(1-Glycerol)); 1,2- Dimyristoyl-Sn-Glycero-3-Phosphocholine; Acetic Acid; Acetic Acid, Glacial; Activated Charcoal; Alanine; Albumin Human; Alcohol; Alcohol, Dehydrated; Ammonium Acetate; Anhydrous Citric Acid; Anhydrous Dextrose; Anhydrous Lactose; Anhydrous Trisodium Citrate; Arginine; Ascorbic Acid; Aspartic Acid; Benzenesulfonic Acid; Benzethonium Chloride; Benzoic Acid; Benzyl Alcohol; Brocrinat; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carbon Dioxide; Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Citric Acid, Hydrous; Cysteine; Cysteine Hydrochloride; Deoxycholic Acid; Dextrose; Dextrose Solution; Diatrizoic Acid; Diethanolamine; Dimethyl Sulfoxide; Disodium Sulfosalicylate; Disofenin; Edetate Calcium Disodium; Edetate Disodium; Edetate Disodium Anhydrous; Edetate Sodium; Egg Phospholipids; Ethylenediamine; Fructose; Gelatin; Gentisic Acid Ethanolamide; Glycerin; Glycine; Histidine; Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydroxide Ion; Hydroxypropyl- Bcyclodextrin; Isoleucine; Isotonic Sodium Chloride Solution; Lactic Acid; Lactic Acid, Dl-; Lactobionic Acid; Lactose; Lactose Monohydrate; Lactose, Hydrous; Leucine; Lysine; Lysine Acetate; Magnesium Chloride; Maleic Acid; Mannitol; Meglumine; Metacresol; Metaphosphoric Acid; Methanesulfonic Acid; Methionine; Methylparaben; Monothioglycerol; N,N-Dimethylacetamide; Nitric Acid; Nitrogen; Peg Vegetable Oil; Peg-40 Castor Oil; Peg-60 Castor Oil; Pentetate Calcium Trisodium; Phenol; Phenylalanine; Phospholipid; Phospholipid, Egg; Phosphoric Acid; Polyethylene Glycol 300; Polyethylene Glycol 400; Polyoxyl 35 Castor Oil; Polysorbate 20; Polysorbate 80; Potassium Chloride; Potassium Hydroxide; Potassium Metabisulfite; Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic; Povidones; Proline; Propylene Glycol; Propylparaben; Saccharin Sodium; Saccharin Sodium Anhydrous; Serine; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfite; Sodium Carbonate; Sodium Chlorate; Sodium Chloride; Sodium Cholesteryl Sulfate; Sodium Citrate; Sodium Desoxycholate; Sodium Dithionite; Sodium Formaldehyde Sulfoxylate; Sodium Gluconate; Sodium Hydroxide; Sodium Hypochlorite; Sodium Lactate; Sodium Lactate, L-; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfite; Sodium Tartrate; Sorbitol; Sorbitol Solution; Soybean Oil; Stannous Chloride; Stannous Chloride Anhydrous; Sterile Water For Inhalation; Sucrose; Sulfobutylether .Beta.-Cyclodextrin; Sulfur Dioxide; Sulfuric Acid; Tartaric Acid; Tartaric Acid, Dl-; Tert-Butyl Alcohol; Tetrofosmin; Theophylline; Threonine; Trifluoroacetic Acid; Trisodium Citrate Dihydrate; Tromethamine; Tryptophan; Tyrosine; Valine Any Delivery Route Alcohol; Benzyl Alcohol; Citric Acid Monohydrate; Gelfoam Sponge; Hydrochloric Acid; Methylparaben; Poly(Dl-Lactic-Co-Glycolic Acid), (50:50; Poly(Dl-Lactic-Co-Glycolic Acid), Ethyl Ester Terminated, (50:50; Polyquaternium-7 (70/30 Acrylamide/Dadmac; Propylene Glycol; Propylparaben; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate; Sodium Phosphate, Monobasic, Monohydrate Nasal Acetic Acid; Alcohol, Dehydrated; Allyl .Alpha.-Ionone; Anhydrous Dextrose; Anhydrous Trisodium Citrate; Benzalkonium Chloride; Benzethonium Chloride; Benzyl Alcohol; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Caffeine; Carbon Dioxide; Carboxymethylcellulose Sodium; Cellulose, Microcrystalline; Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Dextrose; Dichlorodifluoromethane; Dichlorotetrafluoroethane; Edetate Disodium; Glycerin; Glycerol Ester Of Hydrogenated Rosin; Hydrochloric Acid; Hypromellose 2910 (15000 Mpa · S); Methylcelluloses; Methylparaben; Nitrogen; Norflurane; Oleic Acid; Petrolatum, White; Phenylethyl Alcohol; Polyethylene Glycol 3350; Polyethylene Glycol 400; Polyoxyl 400 Stearate; Polysorbate 20; Polysorbate 80; Potassium Phosphate, Monobasic; Potassium Sorbate; Propylene Glycol; Propylparaben; Sodium Acetate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Dodecahydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate; Sorbitan Trioleate; Sorbitol; Sorbitol Solution; Sucralose; Sulfuric Acid; Trichloromonofluoromethane; Trisodium Citrate Dihydrate Nerve Block Acetic Acid; Acetone Sodium Bisulfite; Ascorbic Acid; Benzyl Alcohol; Calcium Chloride; Carbon Dioxide; Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Hydrochloric Acid, Diluted; Lactic Acid; Methylparaben; Monothioglycerol; Nitrogen; Potassium Chloride; Potassium Metabisulfite; Potassium Phosphate, Monobasic; Propylparaben; Sodium Bisulfite; Sodium Carbonate; Sodium Chlorate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate; Sodium Lactate, L-; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic, Heptahydrate Ophthalmic Acetic Acid; Alcohol; Alcohol, Dehydrated; Alginic Acid; Amerchol- Cab; Ammonium Hydroxide; Anhydrous Trisodium Citrate; Antipyrine; Benzalkonium Chloride; Benzethonium Chloride; Benzododecinium Bromide; Boric Acid; Caffeine; Calcium Chloride; Carbomer 1342; Carbomer 934p; Carbomer 940; Carbomer Homopolymer Type B (Allyl Pentaerythritol Crosslinked); Carboxymethylcellulose Sodium; Castor Oil; Cetyl Alcohol; Chlorobutanol; Chlorobutanol, Anhydrous; Cholesterol; Citric Acid; Citric Acid Monohydrate; Creatinine; Diethanolamine; Diethylhexyl Phthalate **See Cder Guidance: Limiting The Use Of Certain Phthalates As Excipients In Cder-Regulated Products; Divinylbenzene Styrene Copolymer; Edetate Disodium; Edetate Disodium Anhydrous; Edetate Sodium; Ethylene Vinyl Acetate Copolymer; Gellan Gum (Low Acyl); Glycerin; Glyceryl Stearate; High Density Polyethylene; Hydrocarbon Gel, Plasticized; Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydroxyethyl Cellulose; Hydroxypropyl Methylcellulose 2906; Hypromellose 2910 (15000 Mpa · S); Hypromelloses; Jelene; Lanolin; Lanolin Alcohols; Lanolin Anhydrous; Lanolin Nonionic Derivatives; Lauralkonium Chloride; Lauroyl Sarcosine; Light Mineral Oil; Magnesium Chloride; Mannitol; Methylcellulose (4000 Mpa · S); Methylcelluloses; Methylparaben; Mineral Oil; Nitric Acid; Nitrogen; Nonoxynol-9; Octoxynol-40; Octylphenol Polymethylene; Petrolatum; Petrolatum, White; Phenylethyl Alcohol; Phenylmercuric Acetate; Phenylmercuric Nitrate; Phosphoric Acid; Polidronium Chloride; Poloxamer 188; Poloxamer 407; Polycarbophil; Polyethylene Glycol 300; Polyethylene Glycol 400; Polyethylene Glycol 8000; Polyoxyethylene - Polyoxypropylene 1800; Polyoxyl 35 Castor Oil; Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Polypropylene Glycol; Polysorbate 20; Polysorbate 60; Polysorbate 80; Polyvinyl Alcohol; Potassium Acetate; Potassium Chloride; Potassium Phosphate, Monobasic; Potassium Sorbate; Povidone K29/32; Povidone K30; Povidone K90; Povidones; Propylene Glycol; Propylparaben; Soda Ash; Sodium Acetate; Sodium Bisulfate; Sodium Bisulfite; Sodium Borate; Sodium Borate Decahydrate; Sodium Carbonate; Sodium Carbonate Monohydrate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sodium Nitrate; Sodium Phosphate; Sodium Phosphate Dihydrate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfate; Sodium Sulfate Anhydrous; Sodium Sulfate Decahydrate; Sodium Sulfite; Sodium Thiosulfate; Sorbic Acid; Sorbitan Monolaurate; Sorbitol; Sorbitol Solution; Stabilized Oxychloro Complex; Sulfuric Acid; Thimerosal; Titanium Dioxide; Tocophersolan; Trisodium Citrate Dihydrate; Triton 720; Tromethamine; Tyloxapol; Zinc Chloride Parenteral Hydrochloric Acid; Mannitol; Nitrogen; Sodium Acetate; Sodium Chloride; Sodium Hydroxide Percutaneous Duro-Tak 87-2287; Silicone Adhesive 4102 Perfusion, Biliary Glycerin Perfusion, Cardiac Hydrochloric Acid; Sodium Hydroxide Periarticular Diatrizoic Acid; Edetate Calcium Disodium; Iodine; Meglumine Peridural Citric Acid; Hydrochloric Acid; Methylparaben; Sodium Chloride; Sodium Hydroxide; Sodium Metabisulfite Perineural Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide Periodontal Ethylene Vinyl Acetate Copolymer; Hydrochloric Acid; Methyl Pyrrolidone; Poloxamer 188; Poloxamer 407; Polylactide Photopheresis Acetic Acid; Alcohol, Dehydrated; Propylene Glycol; Sodium Acetate; Sodium Chloride; Sodium Hydroxide Rectal Alcohol; Alcohol, Dehydrated; Aluminum Subacetate; Anhydrous Citric Acid; Aniseed Oil; Ascorbic Acid; Ascorbyl Palmitate; Balsam Peru; Benzoic Acid; Benzyl Alcohol; Bismuth Subgallate; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylparaben; Caramel; Carbomer 934; Carbomer 934p; Carboxypolymethylene; Cerasynt-Se; Cetyl Alcohol; Cocoa Butter; Coconut Oil, Hydrogenated; Coconut Oil/Palm Kernel Oil Glycerides, Hydrogenated; Cola Nitida Seed Extract; D&C Yellow No. 10; Dichlorodifluoromethane; Dichlorotetrafluoroethane; Dimethyldioctadecylammonium Bentonite; Edetate Calcium Disodium; Edetate Disodium; Edetic Acid; Epilactose; Ethylenediamine; Fat, Edible; Fat, Hard; Fd&C Blue No. 1; Fd&C Green No. 3; Fd&C Yellow No. 6; Flavor Fig 827118; Flavor Raspberry Pfc- 8407; Fructose; Galactose; Glycerin; Glyceryl Palmitate; Glyceryl Stearate; Glyceryl Stearate/Peg Stearate; Glyceryl Stearate/Peg-40 Stearate; Glycine; Hydrocarbon; Hydrochloric Acid; Hydrogenated Palm Oil; Hypromelloses; Lactose; Lanolin; Lecithin; Light Mineral Oil; Magnesium Aluminum Silicate; Magnesium Aluminum Silicate Hydrate; Methylparaben; Nitrogen; Palm Kernel Oil; Paraffin; Petrolatum, White; Polyethylene Glycol 1000; Polyethylene Glycol 1540; Polyethylene Glycol 3350; Polyethylene Glycol 400; Polyethylene Glycol 4000; Polyethylene Glycol 6000; Polyethylene Glycol 8000; Polysorbate 60; Polysorbate 80; Potassium Acetate; Potassium Metabisulfite; Propylene Glycol; Propylparaben; Saccharin Sodium; Saccharin Sodium Anhydrous; Silicon Dioxide, Colloidal; Simethicone; Sodium Benzoate; Sodium Carbonate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sorbitan Monooleate; Sorbitan Sesquioleate; Sorbitol; Sorbitol Solution; Starch; Steareth-10; Steareth- 40; Sucrose; Tagatose, D-; Tartaric Acid, Dl-; Trolamine; Tromethamine; Vegetable Oil Glyceride, Hydrogenated; Vegetable Oil, Hydrogenated; Wax, Emulsifying; White Wax; Xanthan Gum; Zinc Oxide Respiratory (Inhalation) Alcohol; Alcohol, Dehydrated; Apaflurane; Benzalkonium Chloride; Calcium Carbonate; Edetate Disodium; Gelatin; Glycine; Hydrochloric Acid; Lactose Monohydrate; Lysine Monohydrate; Mannitol; Norflurane; Oleic Acid; Polyethylene Glycol 1000; Povidone K25; Silicon Dioxide, Colloidal; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lauryl Sulfate; Sulfuric Acid; Titanium Dioxide; Tromethamine; Zinc Oxide Retrobulbar Hydrochloric Acid; Sodium Hydroxide Soft Tissue Acetic Acid; Anhydrous Trisodium Citrate; Benzyl Alcohol; Carboxymethylcellulose; Carboxymethylcellulose Sodium; Citric Acid; Creatinine; Edetate Disodium; Hydrochloric Acid; Methylcelluloses; Methylparaben; Myristyl-.Gamma.-Picolinium Chloride; Phenol; Phosphoric Acid; Polyethylene Glycol 3350; Polyethylene Glycol 4000; Polysorbate 80; Propylparaben; Sodium Acetate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Sulfite Spinal Anhydrous Dextrose; Dextrose; Hydrochloric Acid; Sodium Hydroxide Subarachnoid Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide Subconjunctival Benzyl Alcohol; Hydrochloric Acid; Sodium Hydroxide Subcutaneous Acetic Acid; Acetic Acid, Glacial; Albumin Human; Ammonium Hydroxide; Ascorbic Acid; Benzyl Alcohol; Calcium Chloride; Carboxymethylcellulose Sodium; Chlorobutanol; Cresol; Diatrizoic Acid; Dimethyl Sulfoxide; Edetate Calcium Disodium; Edetate Disodium; Ethylene Vinyl Acetate Copolymer; Glycerin; Glycine; Glycine Hydrochloride; Histidine; Hydrochloric Acid; Lactic Acid; Lactic Acid, L-; Lactose; Magnesium Chloride; Magnesium Stearate; Mannitol; Metacresol; Methanesulfonic Acid; Methionine; Methyl Pyrrolidone; Methylparaben; Nitrogen; Phenol; Phenol, Liquefied; Phosphoric Acid; Poloxamer 188; Polyethylene Glycol 3350; Polyglactin; Polysorbate 20; Polysorbate 80; Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic; Povidone K17; Povidones; Propylene Glycol; Propylparaben; Protamine Sulfate; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Bicarbonate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate Dihydrate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfite; Sodium Thioglycolate; Stearic Acid; Sucrose; Thimerosal; Tromethamine; Zinc; Zinc Acetate; Zinc Carbonate; Zinc Chloride; Zinc Oxide Sublingual Alcohol, Dehydrated Submucosal Acetic Acid; Edetic Acid; Mannitol; Nitrogen; Sodium Acetate; Sodium Chloride; Sodium Hydroxide; Sodium Metabisulfite Topical .Alpha.-Terpineol; .Alpha.-Tocopherol; .Alpha.-Tocopherol Acetate, Dl-; .Alpha.-Tocopherol, Dl-; 1,2,6-Hexanetriol; 1-O-Tolylbiguanide; 2- Ethyl-1,6-Hexanediol; Acetic Acid; Acetone; Acetylated Lanolin Alcohols; Acrylates Copolymer; Adhesive Tape; Alcohol; Alcohol, Dehydrated; Alcohol, Denatured; Alcohol, Diluted; Alkyl Ammonium Sulfonic Acid Betaine; Alkyl Aryl Sodium Sulfonate; Allantoin; Almond Oil; Aluminum Acetate; Aluminum Chlorhydroxy Allantoinate; Aluminum Hydroxide; Aluminum Hydroxide - Sucrose, Hydrated; Aluminum Hydroxide Gel; Aluminum Hydroxide Gel F 500; Aluminum Hydroxide Gel F 5000; Aluminum Monostearate; Aluminum Oxide; Aluminum Silicate; Aluminum Starch Octenylsuccinate; Aluminum Stearate; Aluminum Sulfate Anhydrous; Amerchol C; Amerchol-Cab; Aminomethylpropanol; Ammonia Solution; Ammonia Solution, Strong; Ammonium Hydroxide; Ammonium Lauryl Sulfate; Ammonium Nonoxynol-4 Sulfate; Ammonium Salt Of C-12-C-15 Linear Primary Alcohol Ethoxylate; Ammonyx; Amphoteric-2; Amphoteric-9; Anhydrous Citric Acid; Anhydrous Trisodium Citrate; Anoxid Sbn; Antifoam; Apricot Kernel Oil Peg-6 Esters; Aquaphor; Arlacel; Ascorbic Acid; Ascorbyl Palmitate; Beeswax; Beeswax, Synthetic; Beheneth-10; Bentonite; Benzalkonium Chloride; Benzoic Acid; Benzyl Alcohol; Betadex; Boric Acid; Butane; Butyl Alcohol; Butyl Ester Of Vinyl Methyl Ether/Maleic Anhydride Copolymer (125000 Mw); Butyl Stearate; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylene Glycol; Butylparaben; C20-40 Pareth-24; Calcium Chloride; Calcium Hydroxide; Canada Balsam; Caprylic/Capric Triglyceride; Caprylic/Capric/Stearic Triglyceride; Captan; Caramel; Carbomer 1342; Carbomer 1382; Carbomer 934; Carbomer 934p; Carbomer 940; Carbomer 941; Carbomer 980; Carbomer 981; Carbomer Homopolymer Type B (Allyl Pentaerythritol Crosslinked); Carbomer Homopolymer Type C (Allyl Pentaerythritol Crosslinked); Carboxy Vinyl Copolymer; Carboxymethylcellulose; Carboxymethylcellulose Sodium; Carboxypolymethylene; Carrageenan; Carrageenan Salt; Castor Oil; Cedar Leaf Oil; Cellulose; Cerasynt-Se; Ceresin; Ceteareth-12; Ceteareth-15; Ceteareth-30; Cetearyl Alcohol/Ceteareth-20; Cetearyl Ethylhexanoate; Ceteth-10; Ceteth-2; Ceteth-20; Ceteth-23; Cetostearyl Alcohol; Cetrimonium Chloride; Cetyl Alcohol; Cetyl Esters Wax; Cetyl Palmitate; Chlorobutanol; Chlorocresol; Chloroxylenol; Cholesterol; Choleth-24; Citric Acid; Citric Acid Monohydrate; Cocamide Ether Sulfate; Cocamine Oxide; Coco Betaine; Coco Diethanolamide; Coco Monoethanolamide; Cocoa Butter; Coco-Glycerides; Coconut Oil; Cocoyl Caprylocaprate; Collagen; Coloring Suspension; Cream Base; Creatinine; Crospovidone; Cyclomethicone; Cyclomethicone/Dimethicone Copolyol; D&C Red No. 28; D&C Red No. 33; D&C Red No. 36; D&C Red No. 39; D&C Yellow No. 10; Decyl Methyl Sulfoxide; Dehydag Wax Sx; Dehydroacetic Acid; Dehymuls E; Denatonium Benzoate; Dextrin; Diazolidinyl Urea; Dichlorobenzyl Alcohol; Dichlorodifluoromethane; Dichlorotetrafluoroethane; Diethanolamine; Diethyl Sebacate; Diethylene Glycol Monoethyl Ether; Dihydroxyaluminum Aminoacetate; Diisopropanolamine; Diisopropyl Adipate; Diisopropyl Dilinoleate; Dimethicone 350; Dimethicone Copolyol; Dimethicone Medical Fluid 360; Dimethyl Isosorbide; Dimethyl Sulfoxide; Dinoseb Ammonium Salt; Disodium Cocoamphodiacetate; Disodium Laureth Sulfosuccinate; Disodium Lauryl Sulfosuccinate; Dmdm Hydantoin; Docosanol; Docusate Sodium; Edetate Disodium; Edetate Sodium; Edetic Acid; Entsufon; Entsufon Sodium; Epitetracycline Hydrochloride; Essence Bouquet 9200; Ethyl Acetate; Ethylcelluloses; Ethylene Glycol; Ethylenediamine; Ethylenediamine Dihydrochloride; Ethylhexyl Hydroxystearate; Ethylparaben; Fatty Acid Pentaerythriol Ester; Fatty Acids; Fatty Alcohol Citrate; Fd&C Blue No. 1; Fd&C Red No. 4; Fd&C Red No. 40; Fd&C Yellow No. 10 (Delisted); Fd&C Yellow No. 5; Fd&C Yellow No. 6; Ferric Oxide; Flavor Rhodia Pharmaceutical No. Rf 451; Formaldehyde; Formaldehyde Solution; Fractionated Coconut Oil; Fragrance 3949-5; Fragrance 520a; Fragrance 6.007; Fragrance 91-122; Fragrance 9128-Y; Fragrance 93498g; Fragrance Balsam Pine No. 5124; Fragrance Bouquet 10328; Fragrance Chemoderm 6401-B; Fragrance Chemoderm 6411; Fragrance Cream No. 73457; Fragrance Cs-28197; Fragrance Felton 066m; Fragrance Firmenich 47373; Fragrance Givaudan Ess 9090/1c; Fragrance H-6540; Fragrance Herbal 10396; Fragrance Nj-1085; Fragrance P O Fl-147; Fragrance Pa 52805; Fragrance Pera Derm D; Fragrance Rbd-9819; Fragrance Shaw Mudge U-7776; Fragrance Tf 044078; Fragrance Ungerer Honeysuckle K 2771; Fragrance Ungerer N5195; Gelatin; Gluconolactone; Glycerin; Glyceryl Citrate; Glyceryl Isostearate; Glyceryl Monostearate; Glyceryl Oleate; Glyceryl Oleate/Propylene Glycol; Glyceryl Palmitate; Glyceryl Ricinoleate; Glyceryl Stearate; Glyceryl Stearate - Laureth-23; Glyceryl Stearate/Peg-100 Stearate; Glyceryl Stearate-Stearamidoethyl Diethylamine; Glycol Distearate; Glycol Stearate; Guar Gum; Hair Conditioner (18n195-1m); Hexylene Glycol; High Density Polyethylene; Hyaluronate Sodium; Hydrocarbon Gel, Plasticized; Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydrogen Peroxide; Hydrogenated Castor Oil; Hydrogenated Palm/Palm Kernel Oil Peg-6 Esters; Hydroxyethyl Cellulose; Hydroxymethyl Cellulose; Hydroxyoctacosanyl Hydroxystearate; Hydroxypropyl Cellulose; Hypromelloses; Imidurea; Irish Moss Extract; Isobutane; Isoceteth-20; Isooctyl Acrylate; Isopropyl Alcohol; Isopropyl Isostearate; Isopropyl Myristate; Isopropyl Myristate - Myristyl Alcohol; Isopropyl Palmitate; Isopropyl Stearate; Isostearic Acid; Isostearyl Alcohol; Jelene; Kaolin; Kathon Cg; Kathon Cg Ii; Lactate; Lactic Acid; Lactic Acid, Dl-; Laneth; Lanolin; Lanolin Alcohol - Mineral Oil; Lanolin Alcohols; Lanolin Anhydrous; Lanolin Cholesterols; Lanolin, Ethoxylated; Lanolin, Hydrogenated; Lauramine Oxide; Laurdimonium Hydrolyzed Animal Collagen; Laureth Sulfate; Laureth-2; Laureth-23; Laureth-4; Lauric Diethanolamide; Lauric Myristic Diethanolamide; Lauryl Sulfate; Lavandula Angustifolia Flowering Top; Lecithin; Lecithin Unbleached; Lemon Oil; Light Mineral Oil; Light Mineral Oil (85 Ssu); Limonene, (+/−)-; Lipocol Sc- 15; Magnesium Aluminum Silicate; Magnesium Aluminum Silicate Hydrate; Magnesium Nitrate; Magnesium Stearate; Mannitol; Maprofix; Medical Antiform A-F Emulsion; Menthol; Methyl Gluceth-10; Methyl Gluceth-20; Methyl Gluceth-20 Sesquistearate; Methyl Glucose Sesquistearate; Methyl Salicylate; Methyl Stearate; Methylcelluloses; Methylchloroisothiazolinone; Methylisothiazolinone; Methylparaben; Microcrystalline Wax; Mineral Oil; Mono And Diglyceride; Monostearyl Citrate; Multisterol Extract; Myristyl Alcohol; Myristyl Lactate; Niacinamide; Nitric Acid; Nitrogen; Nonoxynol Iodine; Nonoxynol-15; Nonoxynol-9; Oatmeal; Octadecene-1/Maleic Acid Copolymer; Octoxynol-1; Octoxynol-9; Octyldodecanol; Oleic Acid; Oleth-10/Oleth- 5; Oleth-2; Oleth-20; Oleyl Alcohol; Oleyl Oleate; Olive Oil; Palmitamine Oxide; Parabens; Paraffin; Paraffin, White Soft; Parfum Creme 45/3; Peanut Oil; Peanut Oil, Refined; Pectin; Peg 6-32 Stearate/Glycol Stearate; Peg-100 Stearate; Peg-12 Glyceryl Laurate; Peg-120 Glyceryl Stearate; Peg-120 Methyl Glucose Dioleate; Peg-15 Cocamine; Peg-150 Distearate; Peg-2 Stearate; Peg-22 Methyl Ether/Dodecyl Glycol Copolymer; Peg-25 Propylene Glycol Stearate; Peg-4 Dilaurate; Peg-4 Laurate; Peg-45/Dodecyl Glycol Copolymer; Peg-5 Oleate; Peg-50 Stearate; Peg-54 Hydrogenated Castor Oil; Peg-6 Isostearate; Peg-60 Hydrogenated Castor Oil; Peg-7 Methyl Ether; Peg- 75 Lanolin; Peg-8 Laurate; Peg-8 Stearate; Pegoxol 7 Stearate; Pentaerythritol Cocoate; Peppermint Oil; Perfume 25677; Perfume Bouquet; Perfume E-1991; Perfume Gd 5604; Perfume Tana 90/42 Scba; Perfume W-1952-1; Petrolatum; Petrolatum, White; Petroleum Distillates; Phenonip; Phenoxyethanol; Phenylmercuric Acetate; Phosphoric Acid; Pine Needle Oil (Pinus Sylvestris); Plastibase-50w; Polidronium Chloride; Poloxamer 124; Poloxamer 181; Poloxamer 182; Poloxamer 188; Poloxamer 237; Poloxamer 407; Polycarbophil; Polyethylene Glycol 1000; Polyethylene Glycol 1450; Polyethylene Glycol 1500; Polyethylene Glycol 1540; Polyethylene Glycol 200; Polyethylene Glycol 300; Polyethylene Glycol 300-1600; Polyethylene Glycol 3350; Polyethylene Glycol 400; Polyethylene Glycol 4000; Polyethylene Glycol 540; Polyethylene Glycol 600; Polyethylene Glycol 6000; Polyethylene Glycol 8000; Polyethylene Glycol 900; Polyhydroxyethyl Methacrylate; Polyisobutylene; Polyisobutylene (1100000 Mw); Polyoxyethylene - Polyoxypropylene 1800; Polyoxyethylene Alcohols; Polyoxyethylene Fatty Acid Esters; Polyoxyethylene Propylene; Polyoxyl 20 Cetostearyl Ether; Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Polyoxyl 400 Stearate; Polyoxyl 6 And Polyoxyl 32 Palmitostearate; Polyoxyl Distearate; Polyoxyl Glyceryl Stearate; Polyoxyl Lanolin; Polyoxyl Stearate; Polypropylene; Polyquaternium-10; Polysorbate 20; Polysorbate 40; Polysorbate 60; Polysorbate 65; Polysorbate 80; Polyvinyl Alcohol; Potash; Potassium Citrate; Potassium Hydroxide; Potassium Soap; Potassium Sorbate; Povidone Acrylate Copolymer; Povidone Hydrogel; Povidone K90; Povidone/Eicosene Copolymer; Povidones; Ppg-12/Smdi Copolymer; Ppg-15 Stearyl Ether; Ppg-20 Methyl Glucose Ether Distearate; Ppg-26 Oleate; Product Wat; Promulgen D; Promulgen G; Propane; Propellant A-46; Propyl Gallate; Propylene Carbonate; Propylene Glycol; Propylene Glycol Diacetate; Propylene Glycol Dicaprylate; Propylene Glycol Monopalmitostearate; Propylene Glycol Palmitostearate; Propylene Glycol Ricinoleate; Propylene Glycol/Diazolidinyl Urea/Methylparaben/Propylparben; Propylparaben; Protein Hydrolysate; Quaternium-15; Quaternium-15 Cis-Form; Quaternium-52; Saccharin; Saccharin Sodium; Safflower Oil; Sd Alcohol 3a; Sd Alcohol 40; Sd Alcohol 40-2; Sd Alcohol 40b; Sepineo P 600; Shea Butter; Silicon; Silicon Dioxide; Silicone; Silicone Adhesive Bio- Psa Q7-4201; Silicone Adhesive Bio-Psa Q7-4301; Silicone Emulsion; Simethicone; Simethicone Emulsion; Sipon Ls 20np; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Alkyl Sulfate; Sodium Benzoate; Sodium Bisulfite; Sodium Borate; Sodium Cetostearyl Sulfate; Sodium Chloride; Sodium Citrate; Sodium Cocoyl Sarcosinate; Sodium Dodecylbenzenesulfonate; Sodium Formaldehyde Sulfoxylate; Sodium Hydroxide; Sodium Iodide; Sodium Lactate; Sodium Laureth-2 Sulfate; Sodium Laureth-3 Sulfate; Sodium Laureth-5 Sulfate; Sodium Lauroyl Sarcosinate; Sodium Lauryl Sulfate; Sodium Lauryl Sulfoacetate; Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate; Sodium Polyacrylate (2500000 Mw); Sodium Pyrrolidone Carboxylate; Sodium Sulfite; Sodium Sulfosuccinated Undecyclenic Monoalkylolamide; Sodium Thiosulfate; Sodium Xylenesulfonate; Somay 44; Sorbic Acid; Sorbitan; Sorbitan Isostearate; Sorbitan Monolaurate; Sorbitan Monooleate; Sorbitan Monopalmitate; Sorbitan Monostearate; Sorbitan Sesquioleate; Sorbitan Tristearate; Sorbitol; Sorbitol Solution; Soybean Flour; Soybean Oil; Spearmint Oil; Spermaceti; Squalane; Starch; Stearalkonium Chloride; Stearamidoethyl Diethylamine; Steareth-10; Steareth-100; Steareth-2; Steareth-20; Steareth-21; Steareth-40; Stearic Acid; Stearic Diethanolamide; Stearoxytrimethylsilane; Steartrimonium Hydrolyzed Animal Collagen; Stearyl Alcohol; Styrene/Isoprene/Styrene Block Copolymer; Sucrose; Sucrose Distearate; Sucrose Polyesters; Sulfacetamide Sodium; Sulfuric Acid; Surfactol Qs; Talc; Tall Oil; Tallow Glycerides; Tartaric Acid; Tenox; Tenox-2; Tert-Butyl Alcohol; Tert-Butyl Hydroperoxide; Thimerosal; Titanium Dioxide; Tocopherol; Tocophersolan; Trichloromonofluoromethane; Trideceth-10; Triethanolamine Lauryl Sulfate; Triglycerides, Medium Chain; Trihydroxystearin; Trilaneth-4 Phosphate; Trilaureth-4 Phosphate; Trisodium Citrate Dihydrate; Trisodium Hedta; Triton X-200; Trolamine; Tromethamine; Tyloxapol; Undecylenic Acid; Vegetable Oil; Vegetable Oil, Hydrogenated; Viscarin; Vitamin E; Wax, Emulsifying; Wecobee Fs; White Wax; Xanthan Gum; Zinc Acetate Transdermal Acrylates Copolymer; Acrylic Acid-Isooctyl Acrylate Copolymer; Acrylic Adhesive 788; Adcote 72a103; Aerotex Resin 3730; Alcohol; Alcohol, Dehydrated; Aluminum Polyester; Bentonite; Butylated Hydroxytoluene; Butylene Glycol; Butyric Acid; Caprylic/Capric Triglyceride; Carbomer 1342; Carbomer 940; Carbomer 980; Carrageenan; Cetylpyridinium Chloride; Citric Acid; Crospovidone; Daubert 1-5 Pestr (Matte) 164z; Diethylene Glycol Monoethyl Ether; Diethylhexyl Phthalate **See Cder Guidance: Limiting The Use Of Certain Phthalates As Excipients In Cder-Regulated Products; Dimethicone Copolyol; Dimethicone Mdx4-4210; Dimethicone Medical Fluid 360; Dimethylaminoethyl Methacrylate - Butyl Methacrylate - Methyl Methacrylate Copolymer; Dipropylene Glycol; Duro-Tak 280- 2516; Duro-Tak 387-2516; Duro-Tak 80-1196; Duro-Tak 87-2070; Duro-Tak 87-2194; Duro-Tak 87-2287; Duro-Tak 87-2296; Duro-Tak 87-2888; Duro-Tak 87-2979; Edetate Disodium; Ethyl Acetate; Ethyl Oleate; Ethylcelluloses; Ethylene Vinyl Acetate Copolymer; Ethylene- Propylene Copolymer; Fatty Acid Esters; Gelva 737; Glycerin; Glyceryl Laurate; Glyceryl Oleate; Heptane; High Density Polyethylene; Hydrochloric Acid; Hydrogenated Polybutene 635-690; Hydroxyethyl Cellulose; Hydroxypropyl Cellulose; Isopropyl Myristate; Isopropyl Palmitate; Lactose; Lanolin Anhydrous; Lauryl Lactate; Lecithin; Levulinic Acid; Light Mineral Oil; Medical Adhesive Modified S-15; Methyl Alcohol; Methyl Laurate; Mineral Oil; Nitrogen; Octisalate; Octyldodecanol; Oleic Acid; Oleyl Alcohol; Oleyl Oleate; Pentadecalactone; Petrolatum, White; Polacrilin; Polyacrylic Acid (250000 Mw); Polybutene (1400 Mw); Polyester; Polyester Polyamine Copolymer; Polyester Rayon; Polyethylene Terephthalates; Polyisobutylene; Polyisobutylene (1100000 Mw); Polyisobutylene (35000 Mw); Polyisobutylene 178-236; Polyisobutylene 241-294; Polyisobutylene 35-39; Polyisobutylene Low Molecular Weight; Polyisobutylene Medium Molecular Weight; Polyisobutylene/Polybutene Adhesive; Polypropylene; Polyvinyl Acetate; Polyvinyl Alcohol; Polyvinyl Chloride; Polyvinyl Chloride-Polyvinyl Acetate Copolymer; Polyvinylpyridine; Povidone K29/32; Povidones; Propylene Glycol; Propylene Glycol Monolaurate; Ra-2397; Ra-3011; Silicon; Silicon Dioxide, Colloidal; Silicone; Silicone Adhesive 4102; Silicone Adhesive 4502; Silicone Adhesive Bio-Psa Q7-4201; Silicone Adhesive Bio-Psa Q7-4301; Silicone/Polyester Film Strip; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sorbitan Monooleate; Stearalkonium Hectorite/Propylene Carbonate; Titanium Dioxide; Triacetin; Trolamine; Tromethamine; Union 76 Amsco-Res 6038; Viscose/Cotton Transmucosal Magnesium Stearate; Mannitol; Potassium Bicarbonate; Sodium Starch Glycolate Ureteral Benzyl Alcohol; Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Meglumine; Methylparaben; Propylparaben; Sodium Citrate; Sodium Hydroxide Urethral Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid; Meglumine; Methylparaben; Polyethylene Glycol 1450; Propylparaben; Sodium Hydroxide; Sodium Phosphate, Dibasic, Heptahydrate; Tromethamine Vaginal Adipic Acid; Alcohol, Denatured; Allantoin; Anhydrous Lactose; Apricot Kernel Oil Peg-6 Esters; Barium Sulfate; Beeswax; Bentonite; Benzoic Acid; Benzyl Alcohol; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Calcium Lactate; Carbomer 934; Carbomer 934p; Cellulose, Microcrystalline; Ceteth-20; Cetostearyl Alcohol; Cetyl Alcohol; Cetyl Esters Wax; Cetyl Palmitate; Cholesterol; Choleth; Citric Acid; Citric Acid Monohydrate; Coconut Oil/Palm Kernel Oil Glycerides, Hydrogenated; Crospovidone; Edetate Disodium; Ethylcelluloses; Ethylene-Vinyl Acetate Copolymer (28% Vinyl Acetate); Ethylene-Vinyl Acetate Copolymer (9% Vinylacetate); Fatty Alcohols; Fd&C Yellow No. 5; Gelatin; Glutamic Acid, Dl-; Glycerin; Glyceryl Isostearate; Glyceryl Monostearate; Glyceryl Stearate; Guar Gum; High Density Polyethylene; Hydrogel Polymer; Hydrogenated Palm Oil; Hypromellose 2208 (15000 Mpa · S); Hypromelloses; Isopropyl Myristate; Lactic Acid; Lactic Acid, Dl-; Lactose; Lactose Monohydrate; Lactose, Hydrous; Lanolin; Lanolin Anhydrous; Lecithin; Lecithin, Soybean; Light Mineral Oil; Magnesium Aluminum Silicate; Magnesium Aluminum Silicate Hydrate; Magnesium Stearate; Methyl Stearate; Methylparaben; Microcrystalline Wax; Mineral Oil; Nitric Acid; Octyldodecanol; Peanut Oil; Peg 6-32 Stearate/Glycol Stearate; Peg-100 Stearate; Peg-120 Glyceryl Stearate; Peg-2 Stearate; Peg-5 Oleate; Pegoxol 7 Stearate; Petrolatum, White; Phenylmercuric Acetate; Phospholipon 90g; Phosphoric Acid; Piperazine Hexahydrate; Poly(Dimethylsiloxane/Methylvinylsiloxane/Methylhydrogensiloxane) Dimethylvinyl Or Dimethylhydroxy Or Trimethyl Endblocked; Polycarbophil; Polyester; Polyethylene Glycol 1000; Polyethylene Glycol 3350; Polyethylene Glycol 400; Polyethylene Glycol 4000; Polyethylene Glycol 6000; Polyethylene Glycol 8000; Polyglyceryl-3 Oleate; Polyglyceryl-4 Oleate; Polyoxyl Palmitate; Polysorbate 20; Polysorbate 60; Polysorbate 80; Polyurethane; Potassium Alum; Potassium Hydroxide; Povidone K29/32; Povidones; Promulgen D; Propylene Glycol; Propylene Glycol Monopalmitostearate; Propylparaben; Quaternium-15 Cis-Form; Silicon Dioxide; Silicon Dioxide, Colloidal; Silicone; Sodium Bicarbonate; Sodium Citrate; Sodium Hydroxide; Sodium Lauryl Sulfate; Sodium Metabisulfite; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Monobasic, Anhydrous; Sorbic Acid; Sorbitan Monostearate; Sorbitol; Sorbitol Solution; Spermaceti; Stannous 2-Ethylhexanoate; Starch; Starch 1500, Pregelatinized; Starch, Corn; Stearamidoethyl Diethylamine; Stearic Acid; Stearyl Alcohol; Tartaric Acid, Dl-; Tert-Butylhydroquinone; Tetrapropyl Orthosilicate; Trolamine; Urea; Vegetable Oil, Hydrogenated; Wecobee Fs; White Ceresin Wax; White Wax

Non-limiting routes of administration for the NAVs of the present invention are described below.

Parenteral and Injectable Administration

Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In certain embodiments for parenteral administration, compositions are mixed with solubilizing agents such as CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.

A pharmaceutical composition for parenteral administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for parenteral administration includes hydrochloric acid, mannitol, nitrogen, sodium acetate, sodium chloride and sodium hydroxide.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables. The sterile formulation may also comprise adjuvants such as local anesthetics, preservatives and buffering agents.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Injectable formulations may be for direct injection into a region of a tissue, organ and/or subject. As a non-limiting example, a tissue, organ and/or subject may be directly injected a formulation by intramyocardial injection into the ischemic region. (See e.g., Zangi et al. Nature Biotechnology 2013; the contents of which are herein incorporated by reference in its entirety).

In order to prolong the effect of an active ingredient, it is often desirable to slow the absorption of the active ingredient from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Rectal and Vaginal Administration

Compositions for rectal or vaginal (e.g., transvaginal) administration are typically suppositories which can be prepared by mixing compositions with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

As a non-limiting example, the formulations for rectal and/or vaginal administration may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and/or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

A pharmaceutical composition for rectal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for rectal administration includes alcohol, alcohol, dehydrated, aluminum subacetate, anhydrous citric acid, aniseed oil, ascorbic acid, ascorbyl palmitate, balsam peru, benzoic acid, benzyl alcohol, bismuth subgallate, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, caramel, carbomer 934, carbomer 934p, carboxypolymethylene, cerasynt-se, cetyl alcohol, cocoa butter, coconut oil, hydrogenated, coconut oil/palm kernel oil glycerides, hydrogenated, cola nitida seed extract, d&c yellow no. 10, dichlorodifluoromethane, dichlorotetrafluoroethane, dimethyldioctadecylammonium bentonite, edetate calcium disodium, edetate disodium, edetic acid, epilactose, ethylenediamine, fat, edible, fat, hard, fd&c blue no. 1, fd&c green no. 3, fd&c yellow no. 6, flavor FIG. 827118, flavor raspberry pfc-8407, fructose, galactose, glycerin, glyceryl palmitate, glyceryl stearate, glyceryl stearate/peg stearate, glyceryl stearate/peg-40 stearate, glycine, hydrocarbon, hydrochloric acid, hydrogenated palm oil, hypromelloses, lactose, lanolin, lecithin, light mineral oil, magnesium aluminum silicate, magnesium aluminum silicate hydrate, methylparaben, nitrogen, palm kernel oil, paraffin, petrolatum, white, polyethylene glycol 1000, polyethylene glycol 1540, polyethylene glycol 3350, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polysorbate 60, polysorbate 80, potassium acetate, potassium metabisulfite, propylene glycol, propylparaben, saccharin sodium, saccharin sodium anhydrous, silicon dioxide, colloidal, simethicone, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate, sodium hydroxide, sodium metabisulfite, sorbitan monooleate, sorbitan sesquioleate, sorbitol, sorbitol solution, starch, steareth-10, steareth-40, sucrose, tagatose, d-, tartaric acid, dl-, trolamine, tromethamine, vegetable oil glyceride, hydrogenated, vegetable oil, hydrogenated, wax, emulsifying, white wax, xanthan gum and zinc oxide.

A pharmaceutical composition for vaginal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for vaginal administration includes adipic acid, alcohol, denatured, allantoin, anhydrous lactose, apricot kernel oil peg-6 esters, barium sulfate, beeswax, bentonite, benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, calcium lactate, carbomer 934, carbomer 934p, cellulose, microcrystalline, ceteth-20, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cholesterol, choleth, citric acid, citric acid monohydrate, coconut oil/palm kernel oil glycerides, hydrogenated, crospovidone, edetate disodium, ethylcelluloses, ethylene-vinyl acetate copolymer (28% vinyl acetate), ethylene-vinyl acetate copolymer (9% vinylacetate), fatty alcohols, fd&c yellow no. 5, gelatin, glutamic acid, dl-, glycerin, glyceryl isostearate, glyceryl monostearate, glyceryl stearate, guar gum, high density polyethylene, hydrogel polymer, hydrogenated palm oil, hypromellose 2208 (15000 mpa·s), hypromelloses, isopropyl myristate, lactic acid, lactic acid, dl-, lactose, lactose monohydrate, lactose, hydrous, lanolin, lanolin anhydrous, lecithin, lecithin, soybean, light mineral oil, magnesium aluminum silicate, magnesium aluminum silicate hydrate, magnesium stearate, methyl stearate, methylparaben, microcrystalline wax, mineral oil, nitric acid, octyldodecanol, peanut oil, peg 6-32 stearate/glycol stearate, peg-100 stearate, peg-120 glyceryl stearate, peg-2 stearate, peg-5 oleate, pegoxol 7 stearate, petrolatum, white, phenylmercuric acetate, phospholipon 90g, phosphoric acid, piperazine hexahydrate, poly(dimethylsiloxane/methylvinylsiloxane/methylhydrogensiloxane) dimethylvinyl or dimethylhydroxy or trimethyl endblocked, polycarbophil, polyester, polyethylene glycol 1000, polyethylene glycol 3350, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyglyceryl-3 oleate, polyglyceryl-4 oleate, polyoxyl palmitate, polysorbate 20, polysorbate 60, polysorbate 80, polyurethane, potassium alum, potassium hydroxide, povidone k29/32, povidones, promulgen d, propylene glycol, propylene glycol monopalmitostearate, propylparaben, quaternium-15 cis-form, silicon dioxide, silicon dioxide, colloidal, silicone, sodium bicarbonate, sodium citrate, sodium hydroxide, sodium lauryl sulfate, sodium metabisulfite, sodium phosphate, dibasic, anhydrous, sodium phosphate, monobasic, anhydrous, sorbic acid, sorbitan monostearate, sorbitol, sorbitol solution, spermaceti, stannous 2-ethylhexanoate, starch, starch 1500, pregelatinized, starch, corn, stearamidoethyl diethylamine, stearic acid, stearyl alcohol, tartaric acid, dl-, tert-butylhydroquinone, tetrapropyl orthosilicate, trolamine, urea, vegetable oil, hydrogenated, wecobee fs, white ceresin wax and white wax.

Oral Administration

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents and/or excipients commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In certain embodiments for parenteral administration, compositions are mixed with solubilizing agents such as CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suspensions for oral dosage may contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be suspending agents, as a non-limiting example the suspending agents may be sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions for oral dosage can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid

The oral dosage may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, an active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient such as sodium citrate or dicalcium phosphate and/or fillers or extenders (e.g. starches, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), humectants (e.g. glycerol), disintegrating agents (e.g. agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarding agents (e.g. paraffin), absorption accelerators (e.g. quaternary ammonium compounds), wetting agents (e.g. cetyl alcohol and glycerol monostearate), absorbents (e.g. kaolin and bentonite clay), and lubricants (e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents. The solid dosage forms may also dissolve once they come in contact with liquid such as, but not limited to, salvia and bile.

Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations.

Solid dosage forms may be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.

Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Dosage forms for oral delivery may also be chewable or may be suckable (e.g., lozenge form). The chewable dosages forms may be sustained release formulations such as, but not limited to, the sustained release compositions described in International Publication No WO2013082470 and US Publication No US20130142876, each of which is herein incorporated by reference in its entirety. The chewable dosage forms may comprise amphipathic lipids such as, but not limited to, those described in International Publication No WO2013082470 and US Publication No US20130142876, each of which is herein incorporated by reference in its entirety.

Topical or Transdermal Administration

As described herein, compositions containing the NAVs of the invention may be formulated for administration transdermally. The skin may be an ideal target site for delivery as it is readily accessible. Gene expression may be restricted not only to the skin, potentially avoiding nonspecific toxicity, but also to specific layers and cell types within the skin.

The site of cutaneous expression of the delivered compositions will depend on the route of nucleic acid delivery. Two routes are commonly considered to deliver NAVs to the skin: (ii) intradermal injection; and (iii) systemic delivery (e.g. for treatment of dermatologic diseases that affect both cutaneous and extracutaneous regions). NAVs can be delivered to the skin by several different approaches known in the art. After delivery of the nucleic acid, gene products have been detected in a number of different skin cell types, including, but not limited to, basal keratinocytes, sebaceous gland cells, dermal fibroblasts and dermal macrophages.

In one embodiment, the invention provides for the NAV compositions to be delivered in more than one injection.

In one embodiment, before transdermal administration at least one area of tissue, such as skin, may be subjected to a device and/or solution which may increase permeability. In one embodiment, the tissue may be subjected to an abrasion device to increase the permeability of the skin (see U.S. Patent Publication No. 20080275468, herein incorporated by reference in its entirety). In another embodiment, the tissue may be subjected to an ultrasound enhancement device. An ultrasound enhancement device may include, but is not limited to, the devices described in U.S. Publication No. 20040236268 and U.S. Pat. Nos. 6,491,657 and 6,234,990; each of which are herein incorporated by reference in their entireties. Methods of enhancing the permeability of tissue are described in U.S. Publication Nos. 20040171980 and 20040236268 and U.S. Pat. No. 6,190,315; each of which are herein incorporated by reference in their entireties.

In one embodiment, a device may be used to increase permeability of tissue before delivering formulations of modified mRNA described herein. The permeability of skin may be measured by methods known in the art and/or described in U.S. Pat. No. 6,190,315, herein incorporated by reference in its entirety. As a non-limiting example, a modified mRNA formulation may be delivered by the drug delivery methods described in U.S. Pat. No. 6,190,315, herein incorporated by reference in its entirety.

In another non-limiting example tissue may be treated with a eutectic mixture of local anesthetics (EMLA) cream before, during and/or after the tissue may be subjected to a device which may increase permeability. Katz et al. (Anesth Analg (2004); 98:371-76; herein incorporated by reference in its entirety) showed that using the EMLA cream in combination with a low energy, an onset of superficial cutaneous analgesia was seen as fast as 5 minutes after a pretreatment with a low energy ultrasound.

In one embodiment, enhancers may be applied to the tissue before, during, and/or after the tissue has been treated to increase permeability. Enhancers include, but are not limited to, transport enhancers, physical enhancers, and cavitation enhancers. Non-limiting examples of enhancers are described in U.S. Pat. No. 6,190,315, herein incorporated by reference in its entirety.

In one embodiment, a device may be used to increase permeability of tissue before delivering formulations of NAVs described herein, which may further contain a substance that invokes an immune response. In another non-limiting example, a formulation containing a substance to invoke an immune response may be delivered by the methods described in U.S. Publication Nos. 20040171980 and 20040236268; each of which are herein incorporated by reference in their entireties.

Dosage forms for transdermal administration of a composition may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, an active ingredient is admixed under sterile conditions with a pharmaceutically acceptable excipient and/or any needed preservatives and/or buffers as may be required.

Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms may be prepared, for example, by dissolving and/or dispensing the compound in the proper medium. Alternatively or additionally, rate may be controlled by either providing a rate controlling membrane and/or by dispersing the compound in a polymer matrix and/or gel.

A pharmaceutical NAV composition for transdermal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for transdermal administration includes acrylates copolymer, acrylic acid-isooctyl acrylate copolymer, acrylic adhesive 788, adcote 72a103, aerotex resin 3730, alcohol, alcohol, dehydrated, aluminum polyester, bentonite, butylated hydroxytoluene, butylene glycol, butyric acid, caprylic/capric triglyceride, carbomer 1342, carbomer 940, carbomer 980, carrageenan, cetylpyridinium chloride, citric acid, crospovidone, daubert 1-5 pestr (matte) 164z, diethylene glycol monoethyl ether, diethylhexyl phthalate, dimethicone copolyol, dimethicone mdx4-4210, dimethicone medical fluid 360, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, dipropylene glycol, duro-tak 280-2516, duro-tak 387-2516, duro-tak 80-1196, duro-tak 87-2070, duro-tak 87-2194, duro-tak 87-2287, duro-tak 87-2296, duro-tak 87-2888, duro-tak 87-2979, edetate disodium, ethyl acetate, ethyl oleate, ethylcelluloses, ethylene vinyl acetate copolymer, ethylene-propylene copolymer, fatty acid esters, gelva 737, glycerin, glyceryl laurate, glyceryl oleate, heptane, high density polyethylene, hydrochloric acid, hydrogenated polybutene 635-690, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, isopropyl palmitate, lactose, lanolin anhydrous, lauryl lactate, lecithin, levulinic acid, light mineral oil, medical adhesive modified s-15, methyl alcohol, methyl laurate, mineral oil, nitrogen, octisalate, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, pentadecalactone, petrolatum, white, polacrilin, polyacrylic acid (250000 mw), polybutene (1400 mw), polyester, polyester polyamine copolymer, polyester rayon, polyethylene terephthalates, polyisobutylene, polyisobutylene (1100000 mw), polyisobutylene (35000 mw), polyisobutylene 178-236, polyisobutylene 241-294, polyisobutylene 35-39, polyisobutylene low molecular weight, polyisobutylene medium molecular weight, polyisobutylene/polybutene adhesive, polypropylene, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polyvinyl chloride-polyvinyl acetate copolymer, polyvinylpyridine, povidone k29/32, povidones, propylene glycol, propylene glycol monolaurate, ra-2397, ra-3011, silicon, silicon dioxide, colloidal, silicone, silicone adhesive 4102, silicone adhesive 4502, silicone adhesive bio-psa q7-4201, silicone adhesive bio-psa q7-4301, silicone/polyester film strip, sodium chloride, sodium citrate, sodium hydroxide, sorbitan monooleate, stearalkonium hectorite/propylene carbonate, titanium dioxide, triacetin, trolamine, tromethamine, union 76 amsco-res 6038 and viscose/cotton.

A pharmaceutical NAV composition for intradermal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for intradermal administration includes benzalkonium chloride, benzyl alcohol, carboxymethylcellulose sodium, creatinine, edetate disodium, glycerin, hydrochloric acid, metacresol, methylparaben, phenol, polysorbate 80, protamine sulfate, sodium acetate, sodium bisulfite, sodium chloride, sodium hydroxide, sodium phosphate, sodium phosphate, dibasic, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, anhydrous and zinc chloride.

Depot Administration

As described herein, in some embodiments, the composition is formulated in depots for extended release. Generally, a specific organ or tissue (a “target tissue”) is targeted for administration.

In some aspects of the invention, the NAVs are spatially retained within or proximal to a target tissue. Provided are method of providing a composition to a target tissue of a mammalian subject by contacting the target tissue (which contains one or more target cells) with the composition under conditions such that the composition, in particular the nucleic acid component(s) of the composition, is substantially retained in the target tissue, meaning that at least 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the composition is retained in the target tissue. Advantageously, retention is determined by measuring the amount of the nucleic acid present in the composition that enters one or more target cells. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the nucleic acids administered to the subject are present intracellularly at a period of time following administration. For example, intramuscular injection to a mammalian subject is performed using an aqueous composition containing a ribonucleic acid and a transfection reagent, and retention of the composition is determined by measuring the amount of the ribonucleic acid present in the muscle cells.

Aspects of the invention are directed to methods of providing a composition to a target tissue of a mammalian subject, by contacting the target tissue (containing one or more target cells) with the composition under conditions such that the composition is substantially retained in the target tissue. The composition contains an effective amount of a polynucleotides such that the polypeptide of interest is produced in at least one target cell. The compositions generally contain a cell penetration agent, although “naked” NAV (such as nucleic acids without a cell penetration agent or other agent) is also contemplated, and a pharmaceutically acceptable carrier.

In some circumstances, the amount of a protein produced by cells in a tissue is desirably increased. Preferably, this increase in protein production is spatially restricted to cells within the target tissue. Thus, provided are methods of increasing production of a protein of interest in a tissue of a mammalian subject. A composition is provided that contains polynucleotides characterized in that a unit quantity of composition has been determined to produce the polypeptide of interest in a substantial percentage of cells contained within a predetermined volume of the target tissue.

In some embodiments, the NAV composition includes a plurality of different polynucleotides, where one or more than one of the polynucleotides encodes a polypeptide of interest. Optionally, the composition also contains a cell penetration agent to assist in the intracellular delivery of the composition. A determination is made of the dose of the composition required to produce the polypeptide of interest in a substantial percentage of cells contained within the predetermined volume of the target tissue (generally, without inducing significant production of the polypeptide of interest in tissue adjacent to the predetermined volume, or distally to the target tissue). Subsequent to this determination, the determined dose is introduced directly into the tissue of the mammalian subject.

In one embodiment, the invention provides for the NAVs to be delivered in more than one injection or by split dose injections.

In one embodiment, the invention may be retained near target tissue using a small disposable drug reservoir, patch pump or osmotic pump. Non-limiting examples of patch pumps include those manufactured and/or sold by BD® (Franklin Lakes, N.J.), Insulet Corporation (Bedford, Mass.), SteadyMed Therapeutics (San Francisco, Calif.), Medtronic (Minneapolis, Minn.) (e.g., MiniMed), UniLife (York, Pa.), Valeritas (Bridgewater, N.J.), and SpringLeaf Therapeutics (Boston, Mass.). A non-limiting example of an osmotic pump include those manufactured by DURECT® (Cupertino, Calif.) (e.g., DUROS® and ALZET®).

Pulmonary Administration

A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 nm to about 7 nm or from about 1 nm to about 6 nm. Such compositions are suitably in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder and/or using a self propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nm and at least 95% of the particles by number have a diameter less than 7 nm. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nm and at least 90% of the particles by number have a diameter less than 6 nm. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50% to 99.9% (w/w) of the composition, and active ingredient may constitute 0.1% to 20% (w/w) of the composition. A propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

As a non-limiting example, the NAVs described herein may be formulated for pulmonary delivery by the methods described in U.S. Pat. No. 8,257,685; herein incorporated by reference in its entirety.

Pharmaceutical NAV compositions formulated for pulmonary delivery may provide an active ingredient in the form of droplets of a solution and/or suspension. Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. Droplets provided by this route of administration may have an average diameter in the range from about 0.1 nm to about 200 nm.

The compositions and formulations provided herein which may be used for pulmonary delivery may further comprise one or more surfactants. Suitable surfactants or surfactant components for enhancing the uptake of the compositions of the invention include synthetic and natural as well as full and truncated forms of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant Protein E, di-saturated phosphatidylcholine (other than dipalmitoyl), dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine; phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palmitate, cytidine diphosphate (CDP) diacylglycerol, CDP choline, choline, choline phosphate; as well as natural and artificial lamellar bodies which are the natural carrier vehicles for the components of surfactant, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric and polymeric, polyoxyethylene, monomeric and polymeric, poly(vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100 and synthetic surfactants ALEC, Exosurf, Survan and Atovaquone, among others. These surfactants can be used either as single or part of a multiple component surfactant in a formulation, or as covalently bound additions to the 5′ and/or 3′ ends of the nucleic acid component of a pharmaceutical composition herein.

Intranasal, Nasal and Buccal Administration

Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a NAV pharmaceutical composition. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 μm to 500 μm. Such a formulation is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose.

Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods and may, for example, 0.1% to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.

A pharmaceutical NAV composition for inhalation (respiratory) administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for inhalation (respiratory) administration includes acetone sodium bisulfite, acetylcysteine, alcohol, alcohol, dehydrated, ammonia, apaflurane, ascorbic acid, benzalkonium chloride, calcium carbonate, carbon dioxide, cetylpyridinium chloride, chlorobutanol, citric acid, d&c yellow no. 10, dichlorodifluoromethane, dichlorotetrafluoroethane, edetate disodium, edetate sodium, fd&c yellow no. 6, fluorochlorohydrocarbons, gelatin, glycerin, glycine, hydrochloric acid, hydrochloric acid, diluted, lactose, lactose monohydrate, lecithin, lecithin, hydrogenated soy, lecithin, soybean, lysine monohydrate, mannitol, menthol, methylparaben, nitric acid, nitrogen, norflurane, oleic acid, polyethylene glycol 1000, povidone k25, propylene glycol, propylparaben, saccharin, saccharin sodium, silicon dioxide, colloidal, sodium bisulfate, sodium bisulfite, sodium chloride, sodium citrate, sodium hydroxide, sodium lauryl sulfate, sodium metabisulfite, sodium sulfate anhydrous, sodium sulfite, sorbitan trioleate, sulfuric acid, thymol, titanium dioxide, trichloromonofluoromethane, tromethamine and zinc oxide.

A pharmaceutical NAV composition for nasal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for nasal administration includes acetic acid, alcohol, dehydrated, allyl .alpha.-ionone, anhydrous dextrose, anhydrous trisodium citrate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, caffeine, carbon dioxide, carboxymethylcellulose sodium, cellulose, microcrystalline, chlorobutanol, citric acid, citric acid monohydrate, dextrose, dichlorodifluoromethane, dichlorotetrafluoroethane, edetate disodium, glycerin, glycerol ester of hydrogenated rosin, hydrochloric acid, hypromellose 2910 (15000 mpa·s), methylcelluloses, methylparaben, nitrogen, norflurane, oleic acid, petrolatum, white, phenylethyl alcohol, polyethylene glycol 3350, polyethylene glycol 400, polyoxyl 400 stearate, polysorbate 20, polysorbate 80, potassium phosphate, monobasic, potassium sorbate, propylene glycol, propylparaben, sodium acetate, sodium chloride, sodium citrate, sodium hydroxide, sodium phosphate, sodium phosphate, dibasic, sodium phosphate, dibasic, anhydrous, sodium phosphate, dibasic, dihydrate, sodium phosphate, dibasic, dodecahydrate, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, anhydrous, sodium phosphate, monobasic, dihydrate, sorbitan trioleate, sorbitol, sorbitol solution, sucralose, sulfuric acid, trichloromonofluoromethane and trisodium citrate dihydrate.

Ophthalmic and Auricular (Otic) Administration

A pharmaceutical NAV composition may be prepared, packaged, and/or sold in a formulation suitable for delivery to and/or around the eye and/or delivery to the ear (e.g., auricular (otic) administration). Non-limiting examples of route of administration for delivery to and/or around the eye include retrobulbar, conjuctival, intracorneal, intraocular, intravitreal, ophthlamic and subconjuctiva. Such formulations may, for example, be in the form of eye drops or ear drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of any additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention. A multilayer thin film device may be prepared to contain a pharmaceutical composition for delivery to the eye and/or surrounding tissue.

A pharmaceutical NAV composition for ophthalmic administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for ophthalmic administration includes acetic acid, alcohol, alcohol, dehydrated, alginic acid, amerchol-cab, ammonium hydroxide, anhydrous trisodium citrate, antipyrine, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, boric acid, caffeine, calcium chloride, carbomer 1342, carbomer 934p, carbomer 940, carbomer homopolymer type b (allyl pentaerythritol crosslinked), carboxymethylcellulose sodium, castor oil, cetyl alcohol, chlorobutanol, chlorobutanol, anhydrous, cholesterol, citric acid, citric acid monohydrate, creatinine, diethanolamine, diethylhexyl phthalate, divinylbenzene styrene copolymer, edetate disodium, edetate disodium anhydrous, edetate sodium, ethylene vinyl acetate copolymer, gellan gum (low acyl), glycerin, glyceryl stearate, high density polyethylene, hydrocarbon gel, plasticized, hydrochloric acid, hydrochloric acid, diluted, hydroxyethyl cellulose, hydroxypropyl methylcellulose 2906, hypromellose 2910 (15000 mpa·s), hypromelloses, jelene, lanolin, lanolin alcohols, lanolin anhydrous, lanolin nonionic derivatives, lauralkonium chloride, lauroyl sarcosine, light mineral oil, magnesium chloride, mannitol, methylcellulose (4000 mpa·s), methylcelluloses, methylparaben, mineral oil, nitric acid, nitrogen, nonoxynol-9, octoxynol-40, octylphenol polymethylene, petrolatum, petrolatum, white, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, phosphoric acid, polidronium chloride, poloxamer 188, poloxamer 407, polycarbophil, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 8000, polyoxyethylene-polyoxypropylene 1800, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polypropylene glycol, polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol, potassium acetate, potassium chloride, potassium phosphate, monobasic, potassium sorbate, povidone k29/32, povidone k30, povidone k90, povidones, propylene glycol, propylparaben, soda ash, sodium acetate, sodium bisulfate, sodium bisulfite, sodium borate, sodium borate decahydrate, sodium carbonate, sodium carbonate monohydrate, sodium chloride, sodium citrate, sodium hydroxide, sodium metabisulfite, sodium nitrate, sodium phosphate, sodium phosphate dihydrate, sodium phosphate, dibasic, sodium phosphate, dibasic, anhydrous, sodium phosphate, dibasic, dihydrate, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, sodium phosphate, monobasic, anhydrous, sodium phosphate, monobasic, dihydrate, sodium phosphate, monobasic, monohydrate, sodium sulfate, sodium sulfate anhydrous, sodium sulfate decahydrate, sodium sulfite, sodium thiosulfate, sorbic acid, sorbitan monolaurate, sorbitol, sorbitol solution, stabilized oxychloro complex, sulfuric acid, thimerosal, titanium dioxide, tocophersolan, trisodium citrate dihydrate, triton 720, tromethamine, tyloxapol and zinc chloride.

A pharmaceutical NAV composition for retrobulbar administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for retrobulbar administration includes hydrochloric acid and sodium hydroxide.

A pharmaceutical NAV composition for intraocular administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for intraocular administration includes benzalkonium chloride, calcium chloride, citric acid monohydrate, hydrochloric acid, magnesium chloride, polyvinyl alcohol, potassium chloride, sodium acetate, sodium chloride, sodium citrate and sodium hydroxide.

A pharmaceutical NAV composition for intravitreal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for intravitreal administration includes calcium chloride, carboxymethylcellulose sodium, cellulose, microcrystalline, hyaluronate sodium, hydrochloric acid, magnesium chloride, magnesium stearate, polysorbate 80, polyvinyl alcohol, potassium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium chloride, sodium hydroxide, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate and trisodium citrate dehydrate.

A pharmaceutical NAV composition for subconjunctival administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for subconjunctival administration includes benzyl alcohol, hydrochloric acid and sodium hydroxide.

A pharmaceutical NAV composition for auricular administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the U.S. Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for auricular administration includes acetic acid, aluminum acetate, aluminum sulfate anhydrous, benzalkonium chloride, benzethonium chloride, benzyl alcohol, boric acid, calcium carbonate, cetyl alcohol, chlorobutanol, chloroxylenol, citric acid, creatinine, cupric sulfate, cupric sulfate anhydrous, edetate disodium, edetic acid, glycerin, glyceryl stearate, hydrochloric acid, hydrocortisone, hydroxyethyl cellulose, isopropyl myristate, lactic acid, lecithin, hydrogenated, methylparaben, mineral oil, petrolatum, petrolatum, white, phenylethyl alcohol, polyoxyl 40 stearate, polyoxyl stearate, polysorbate 20, polysorbate 80, polyvinyl alcohol, potassium metabisulfite, potassium phosphate, monobasic, povidone k90f, povidones, propylene glycol, propylene glycol diacetate, propylparaben, sodium acetate, sodium bisulfite, sodium borate, sodium chloride, sodium citrate, sodium hydroxide, sodium phosphate, dibasic, anhydrous, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, anhydrous, sodium sulfite, sulfuric acid and thimerosal.

Payload Administration: Detectable Agents and Therapeutic Agents

The NAVs described herein can be used in a number of different scenarios in which delivery of a substance (the “payload”) to a biological target is desired, for example delivery of detectable substances for detection of the target, or delivery of a therapeutic agent. Detection methods can include, but are not limited to, both imaging in vitro and in vivo imaging methods, e.g., immunohistochemistry, bioluminescence imaging (BLI), Magnetic Resonance Imaging (MRI), positron emission tomography (PET), electron microscopy, X-ray computed tomography, Raman imaging, optical coherence tomography, absorption imaging, thermal imaging, fluorescence reflectance imaging, fluorescence microscopy, fluorescence molecular tomographic imaging, nuclear magnetic resonance imaging, X-ray imaging, ultrasound imaging, photoacoustic imaging, lab assays, or in any situation where tagging/staining/imaging is required.

NAVs described herein can be used in intracellular targeting of a payload, e.g., detectable or therapeutic agent, to specific organelle. Exemplary intracellular targets can include, but are not limited to, the nuclear localization for advanced mRNA processing, or a nuclear localization sequence (NLS) linked to the mRNA containing an inhibitor.

In addition, the NAVs described herein can be used to deliver therapeutic agents to cells or tissues, e.g., in living animals. For example, the NAVs described herein can be used to deliver highly polar chemotherapeutics agents to kill cancer cells. The NAVs attached to the therapeutic agent through a linker can facilitate member permeation allowing the therapeutic agent to travel into a cell to reach an intracellular target.

In some embodiments, the payload may be a therapeutic agent such as a cytotoxin, radioactive ion, chemotherapeutic, or other therapeutic agent. A cytotoxin or cytotoxic agent includes any agent that may be detrimental to cells. Examples include, but are not limited to, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracinedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, e.g., maytansinol (see U.S. Pat. No. 5,208,020 incorporated herein in its entirety), rachelmycin (CC-1065, see U.S. Pat. Nos. 5,475,092, 5,585,499, and 5,846,545, all of which are incorporated herein by reference), and analogs or homologs thereof. Radioactive ions include, but are not limited to iodine (e.g., iodine 125 or iodine 131), strontium 89, phosphorous, palladium, cesium, iridium, phosphate, cobalt, yttrium 90, samarium 153, and praseodymium. Other therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thiotepa chlorambucil, rachelmycin (CC-1065), melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine, vinblastine, taxol and maytansinoids).

In some embodiments, the payload may be a detectable agent, such as various organic small molecules, inorganic compounds, nanoparticles, enzymes or enzyme substrates, fluorescent materials, luminescent materials (e.g., luminol), bioluminescent materials (e.g., luciferase, luciferin, and aequorin), chemiluminescent materials, radioactive materials (e.g., ¹⁸F, ⁶⁷Ga, ^(81m)Kr, ⁸²Rb, ¹¹¹In, ¹²³I, ¹³³Xe, ²⁰¹Tl, ¹²⁵I, ³⁵S, ¹⁴C, ³H, or ^(99m)Tc (e.g., as pertechnetate (technetate(VII), TcO₄ ⁻)) and contrast agents (e.g., gold (e.g., gold nanoparticles), gadolinium (e.g., chelated Gd), iron oxides (e.g., superparamagnetic iron oxide (SPIO), monocrystalline iron oxide nanoparticles (MIONs), and ultrasmall superparamagnetic iron oxide (USPIO)), manganese chelates (e.g., Mn-DPDP), barium sulfate, iodinated contrast media (iohexol), microbubbles, or perfluorocarbons). Such optically-detectable labels include for example, without limitation, 4-acetamido-4′-isothiocyanatostilbene-2,2′disulfonic acid; acridine and derivatives (e.g., acridine and acridine isothiocyanate); 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS); 4-amino-N-[3-vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate; N-(4-anilino-1-naphthyl)maleimide; anthranilamide; BODIPY; Brilliant Yellow; coumarin and derivatives (e.g., coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), and 7-amino-4-trifluoromethylcoumarin (Coumarin 151)); cyanine dyes; cyanosine; 4′,6-diaminidino-2-phenylindole (DAPI); 5′ 5″-dibromopyrogallol-sulfonaphthalein (Bromopyrogallol Red); 7-diethylamino-3-(4′-isothiocyanatophenyl)-4-methylcoumarin; diethylenetriamine pentaacetate; 4,4′-diisothiocyanatodihydro-stilbene-2,2′-disulfonic acid; 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid; 5-[dimethylamino]-naphthalene-1-sulfonyl chloride (DNS, dansylchloride); 4-dimethylaminophenylazophenyl-4′-isothiocyanate (DAB ITC); eosin and derivatives (e.g., eosin and eosin isothiocyanate); erythrosin and derivatives (e.g., erythrosin B and erythrosin isothiocyanate); ethidium; fluorescein and derivatives (e.g., 5-carboxyfluorescein (FAM), 5-(4,6-dichlorotriazin-2-yl)aminofluorescein (DTAF), 2′,7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein, fluorescein, fluorescein isothiocyanate, X-rhodamine-5-(and-6)-isothiocyanate (QFITC or XRITC), and fluorescamine); 2-[2-[3-[[1,3-dihydro-1,1-dimethyl-3-(3-sulfopropyl)-2H-benz[e]indol-2-ylidene]ethylidene]-2-[4-(ethoxycarbonyl)-1-piperazinyl]-1-cyclopenten-1-yl]ethenyl]-1,1-dimethyl-3-(3-sulforpropyl)-1H-benz[e]indolium hydroxide, inner salt, compound with n,n-diethylethanamine(1:1) (IR144); 5-chloro-2-[2-[3-[(5-chloro-3-ethyl-2(3H)-benzothiazol-ylidene)ethylidene]-2-(diphenylamino)-1-cyclopenten-1-yl]ethenyl]-3-ethyl benzothiazolium perchlorate (IR140); Malachite Green isothiocyanate; 4-methylumbelliferone orthocresolphthalein; nitrotyrosine; pararosaniline; Phenol Red; B-phycoerythrin; o-phthaldialdehyde; pyrene and derivatives(e.g., pyrene, pyrene butyrate, and succinimidyl 1-pyrene); butyrate quantum dots; Reactive Red 4 (CIBACRON™ Brilliant Red 3B-A); rhodamine and derivatives (e.g., 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), lissamine rhodamine B sulfonyl chloride rhodarnine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, sulforhodamine B, sulforhodamine 101, sulfonyl chloride derivative of sulforhodamine 101 (Texas Red), N,N,N′,N′tetramethyl-6-carboxyrhodamine (TAMRA) tetramethyl rhodamine, and tetramethyl rhodamine isothiocyanate (TRITC)); riboflavin; rosolic acid; terbium chelate derivatives; Cyanine-3 (Cy3); Cyanine-5 (Cy5); cyanine-5.5 (Cy5.5), Cyanine-7 (Cy7); IRD 700; IRD 800; Alexa 647; La Jolta Blue; phthalo cyanine; and naphthalo cyanine.

In some embodiments, the detectable agent may be a non-detectable precursor that becomes detectable upon activation (e.g., fluorogenic tetrazine-fluorophore constructs (e.g., tetrazine-BODIPY FL, tetrazine-Oregon Green 488, or tetrazine-BODIPY TMR-X) or enzyme activatable fluorogenic agents (e.g., PROSENSE® (VisEn Medical))). In vitro assays in which the enzyme labeled compositions can be used include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), immunoprecipitation assays, immunofluorescence, enzyme immunoassays (EIA), radioimmunoassays (RIA), and Western blot analysis.

Combinations

The NAVs may be used in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents. By “in combination with,” it is not intended to imply that the agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the present disclosure. Compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In some embodiments, the present disclosure encompasses the delivery of pharmaceutical, prophylactic, diagnostic, or imaging compositions in combination with agents that may improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.

The combinations can conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

It will further be appreciated that therapeutically, prophylactically, diagnostically, or imaging active agents utilized in combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that agents utilized in combination with be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. In one embodiment, the combinations, each or together may be administered according to the split dosing regimens described herein.

Dosing

The present invention provides methods comprising administering NAVs and in accordance with the invention to a subject in need thereof. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. Compositions in accordance with the invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

In certain embodiments, compositions in accordance with the present invention may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect (see e.g., the range of unit doses described in International Publication No WO2013078199, herein incorporated by reference in its entirety). The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). When multiple administrations are employed, split dosing regimens such as those described herein may be used.

According to the present invention, NAVs may be administered in split-dose regimens. As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses, e.g, two or more administrations of the single unit dose. As used herein, a “single unit dose” is a dose of any therapeutic administed in one dose/at one time/single route/single point of contact, i.e., single administration event. As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose. In one embodiment, the NAVs of the present invention are administed to a subject in split doses. The NAVs may be formulated in buffer only or in a formulation described herein.

Dosage Forms

A NAV pharmaceutical composition described herein can be formulated into a dosage form described herein, such as an intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, subcutaneous).

Liquid Dosage Forms

Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art including, but not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments for parenteral administration, compositions may be mixed with solubilizing agents such as CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.

Injectable

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art and may include suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of an active ingredient, it may be desirable to slow the absorption of the active ingredient from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the NAVs then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered NAV may be accomplished by dissolving or suspending the NAVs in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the NAVs in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of NAVs to polymer and the nature of the particular polymer employed, the rate of polynucleotides release can be controlled. Examples of other biodegradable polymers include, but are not limited to, poly(orthoesters) and poly(anhydrides). Depot injectable formulations may be prepared by entrapping the NAVs in liposomes or microemulsions which are compatible with body tissues.

Pulmonary

Formulations described herein as being useful for pulmonary delivery may also be used for intranasal delivery of a pharmaceutical composition. Another formulation suitable for intranasal administration may be a coarse powder comprising the active ingredient and having an average particle from about 0.2 μm to 500 μm. Such a formulation may be administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose.

Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, contain about 0.1% to 20% (w/w) active ingredient, where the balance may comprise an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.

General considerations in the formulation and/or manufacture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21^(st) ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety).

Coatings or Shells

Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Multi-Dose and Repeat-Dose Administration

In some embodiments, NAV compounds and/or compositions of the present invention may be administered in two or more doses (referred to herein as “multi-dose administration”). Such doses may comprise the same components or may comprise components not included in a previous dose. Such doses may comprise the same mass and/or volume of components or an altered mass and/or volume of components in comparison to a previous dose. In some embodiments, multi-dose administration may comprise repeat-dose administration. As used herein, the term “repeat-dose administration” refers to two or more doses administered consecutively or within a regimen of repeat doses comprising substantially the same components provided at substantially the same mass and/or volume. In some embodiments, subjects may display a repeat-dose response. As used herein, the term “repeat-dose response” refers to a response in a subject to a repeat-dose that differs from that of another dose administered within a repeat-dose administration regimen. In some embodiments, such a response may be the expression of a protein in response to a repeat-dose comprising NAV. In such embodiments, protein expression may be elevated in comparison to another dose administered within a repeat-dose administration regimen or protein expression may be reduced in comparison to another dose administered within a repeat-dose administration regimen. Alteration of protein expression may be from about 1% to about 20%, from about 5% to about 50% from about 10% to about 60%, from about 25% to about 75%, from about 40% to about 100% and/or at least 100%. A reduction in expression of mRNA administered as part of a repeat-dose regimen, wherein the level of protein translated from the administered RNA is reduced by more than 40% in comparison to another dose within the repeat-dose regimen is referred to herein as “repeat-dose resistance.”

Properties of the Pharmaceutical Compositions

The NAV pharmaceutical compositions described herein can be characterized by one or more of the following properties:

Bioavailability

The NAVs, when formulated into a composition with a delivery agent as described herein, can exhibit an increase in bioavailability as compared to a composition lacking a delivery agent as described herein. As used herein, the term “bioavailability” refers to the systemic availability of a given amount of NAVs administered to a mammal. Bioavailability can be assessed by measuring the area under the curve (AUC) or the maximum serum or plasma concentration (C_(max)) of the unchanged form of a compound following administration of the compound to a mammal. AUC is a determination of the area under the curve plotting the serum or plasma concentration of a compound along the ordinate (Y-axis) against time along the abscissa (X-axis). Generally, the AUC for a particular compound can be calculated using methods known to those of ordinary skill in the art and as described in G. S. Banker, Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences, v. 72, Marcel Dekker, N.Y., Inc., 1996, herein incorporated by reference in its entirety.

The C_(max) value is the maximum concentration of the compound achieved in the serum or plasma of a mammal following administration of the compound to the mammal. The C_(max) value of a particular compound can be measured using methods known to those of ordinary skill in the art. The phrases “increasing bioavailability” or “improving the pharmacokinetics,” as used herein mean that the systemic availability of a first NAV, measured as AUC, C_(max), or C_(min) in a mammal is greater, when co-administered with a delivery agent as described herein, than when such co-administration does not take place. In some embodiments, the bioavailability of the NAVs can increase by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.

In some embodiments, liquid formulations of NAVs may have varying in vivo half-life, requiring modulation of doses to yield a therapeutic effect. To address this, in some embodiments of the present invention, NAV formulations may be designed to improve bioavailability and/or therapeutic effect during repeat administrations. Such formulations may enable sustained release of NAVs and/or reduce NAV degradation rates by nucleases. In some embodiments, suspension formulations are provided comprising NAVs, water immiscible oil depots, surfactants and/or co-surfactants and/or co-solvents. Combinations of oils and surfactants may enable suspension formulation with NAVs. Delivery of NAVs in a water immiscible depot may be used to improve bioavailability through sustained release of polynucleotides from the depot to the surrounding physiologic environment and/or prevent polynucleotide degradation by nucleases.

In some embodiments, cationic nanoparticles comprising combinations of divalent and monovalent cations may be formulated with NAVs. Such nanoparticles may form spontaneously in solution over a given period (e.g. hours, days, etc). Such nanoparticles do not form in the presence of divalent cations alone or in the presence of monovalent cations alone. The delivery of NAVs in cationic nanoparticles or in one or more depot comprising cationic nanoparticles may improve NAV bioavailability by acting as a long-acting depot and/or reducing the rate of degradation by nucleases.

Therapeutic Window

The NAVs, when formulated into a composition with a delivery agent as described herein, can exhibit an increase in the therapeutic window of the administered NAV composition as compared to the therapeutic window of the administered NAV composition lacking a delivery agent as described herein. As used herein “therapeutic window” refers to the range of plasma concentrations, or the range of levels of therapeutically active substance at the site of action, with a high probability of eliciting a therapeutic effect. In some embodiments, the therapeutic window of the NAVs when co-administered with a delivery agent as described herein can increase by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.

Volume of Distribution

The NAVs, when formulated into a composition with a delivery agent as described herein, can exhibit an improved volume of distribution (V_(dist)), e.g., reduced or targeted, relative to a composition lacking a delivery agent as described herein. The volume of distribution (V_(dist)) relates the amount of the drug in the body to the concentration of the drug in the blood or plasma. As used herein, the term “volume of distribution” refers to the fluid volume that would be required to contain the total amount of the drug in the body at the same concentration as in the blood or plasma: Vdist equals the amount of drug in the body/concentration of drug in blood or plasma. For example, for a 10 mg dose and a plasma concentration of 10 mg/L, the volume of distribution would be 1 liter. The volume of distribution reflects the extent to which the drug is present in the extravascular tissue. A large volume of distribution reflects the tendency of a compound to bind to the tissue components compared with plasma protein binding. In a clinical setting, Vdist can be used to determine a loading dose to achieve a steady state concentration. In some embodiments, the volume of distribution of the NAVs when co-administered with a delivery agent as described herein can decrease at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%.

Biological Effect

In one embodiment, the biological effect of the NAV delivered to the animals may be categorized by analyzing the protein expression in the animals. The protein expression may be determined from analyzing a biological sample collected from a mammal administered the NAV of the present invention

Detection of Polynucleotides by Mass Spectrometry

Mass spectrometry (MS) is an analytical technique that can provide structural and molecular mass/concentration information on molecules after their conversion to ions. The molecules are first ionized to acquire positive or negative charges and then they travel through the mass analyzer to arrive at different areas of the detector according to their mass/charge (m/z) ratio.

Mass spectrometry is performed using a mass spectrometer which includes an ion source for ionizing the fractionated sample and creating charged molecules for further analysis. For example ionization of the sample may be performed by electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), photoionization, electron ionization, fast atom bombardment (FAB)/liquid secondary ionization (LSIMS), matrix assisted laser desorption/ionization (MALDI), field ionization, field desorption, thermospray/plasmaspray ionization, and particle beam ionization. The skilled artisan will understand that the choice of ionization method can be determined based on the analyte to be measured, type of sample, the type of detector, the choice of positive versus negative mode, etc.

After the sample has been ionized, the positively charged or negatively charged ions thereby created may be analyzed to determine a mass-to-charge ratio (i.e., m/z). Suitable analyzers for determining mass-to-charge ratios include quadropole analyzers, ion traps analyzers, and time-of-flight analyzers. The ions may be detected using several detection modes. For example, selected ions may be detected (i.e., using a selective ion monitoring mode (SIM)), or alternatively, ions may be detected using a scanning mode, e.g., multiple reaction monitoring (MRM) or selected reaction monitoring (SRM).

Liquid chromatography-multiple reaction monitoring (LC-MS/MRM) coupled with stable isotope labeled dilution of peptide standards has been shown to be an effective method for protein verification (e.g., Keshishian et al., Mol Cell Proteomics 2009 8: 2339-2349; Kuhn et al., Clin Chem 2009 55:1108-1117; Lopez et al., Clin Chem 2010 56:281-290; each of which are herein incorporated by reference in its entirety). Unlike untargeted mass spectrometry frequently used in biomarker discovery studies, targeted MS methods are peptide sequence-based modes of MS that focus the full analytical capacity of the instrument on tens to hundreds of selected peptides in a complex mixture. By restricting detection and fragmentation to only those peptides derived from proteins of interest, sensitivity and reproducibility are improved dramatically compared to discovery-mode MS methods. This method of mass spectrometry-based multiple reaction monitoring (MRM) quantitation of proteins can dramatically impact the discovery and quantitation of biomarkers via rapid, targeted, multiplexed protein expression profiling of clinical samples.

In one embodiment, a biological sample which may contain at least one protein encoded by at least one modified mRNA of the present invention may be analyzed by the method of MRM-MS. The quantification of the biological sample may further include, but is not limited to, isotopically labeled peptides or proteins as internal standards.

According to the present invention, the biological sample, once obtained from the subject, may be subjected to enzyme digestion. As used herein, the term “digest” means to break apart into shorter peptides. As used herein, the phrase “treating a sample to digest proteins” means manipulating a sample in such a way as to break down proteins in a sample. These enzymes include, but are not limited to, trypsin, endoproteinase Glu-C and chymotrypsin. In one embodiment, a biological sample which may contain at least one protein encoded by at least one modified mRNA of the present invention may be digested using enzymes.

In one embodiment, a biological sample which may contain protein encoded by modified mRNA of the present invention may be analyzed for protein using electrospray ionization. Electrospray ionization (ESI) mass spectrometry (ESIMS) uses electrical energy to aid in the transfer of ions from the solution to the gaseous phase before they are analyzed by mass spectrometry. Samples may be analyzed using methods known in the art (e.g., Ho et al., Clin Biochem Rev. 2003 24(1):3-12; herein incorporated by reference in its entirety). The ionic species contained in solution may be transferred into the gas phase by dispersing a fine spray of charge droplets, evaporating the solvent and ejecting the ions from the charged droplets to generate a mist of highly charged droplets. The mist of highly charged droplets may be analyzed using at least 1, at least 2, at least 3 or at least 4 mass analyzers such as, but not limited to, a quadropole mass analyzer. Further, the mass spectrometry method may include a purification step. As a non-limiting example, the first quadrapole may be set to select a single m/z ratio so it may filter out other molecular ions having a different m/z ratio which may eliminate complicated and time-consuming sample purification procedures prior to MS analysis.

In one embodiment, a biological sample which may contain protein encoded by modified mRNA of the present invention may be analyzed for protein in a tandem ESIMS system (e.g., MS/MS). As non-limiting examples, the droplets may be analyzed using a product scan (or daughter scan) a precursor scan (parent scan) a neutral loss or a multiple reaction monitoring.

In one embodiment, a biological sample which may contain protein encoded by modified mRNA of the present invention may be analyzed using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MALDIMS). MALDI provides for the nondestructive vaporization and ionization of both large and small molecules, such as proteins. In MALDI analysis, the analyte is first co-crystallized with a large molar excess of a matrix compound, which may also include, but is not limited to, an ultraviolet absorbing weak organic acid. Non-limiting examples of matrices used in MALDI are α-cyano-4-hydroxycinnamic acid, 3,5-dimethoxy-4-hydroxycinnamic acid and 2,5-dihydroxybenzoic acid. Laser radiation of the analyte-matrix mixture may result in the vaporization of the matrix and the analyte. The laser induced desorption provides high ion yields of the intact analyte and allows for measurement of compounds with high accuracy. Samples may be analyzed using methods known in the art (e.g., Lewis, Wei and Siuzdak, Encyclopedia of Analytical Chemistry 2000:5880-5894; herein incorporated by reference in its entirety). As non-limiting examples, mass analyzers used in the MALDI analysis may include a linear time-of-flight (TOF), a TOF reflectron or a Fourier transform mass analyzer.

In one embodiment, the analyte-matrix mixture may be formed using the dried-droplet method. A biologic sample is mixed with a matrix to create a saturated matrix solution where the matrix-to-sample ratio is approximately 5000:1. An aliquot (approximately 0.5-2.0 uL) of the saturated matrix solution is then allowed to dry to form the analyte-matrix mixture.

In one embodiment, the analyte-matrix mixture may be formed using the thin-layer method. A matrix homogeneous film is first formed and then the sample is then applied and may be absorbed by the matrix to form the analyte-matrix mixture.

In one embodiment, the analyte-matrix mixture may be formed using the thick-layer method. A matrix homogeneous film is formed with a nitro-cellulose matrix additive. Once the uniform nitro-cellulose matrix layer is obtained the sample is applied and absorbed into the matrix to form the analyte-matrix mixture.

In one embodiment, the analyte-matrix mixture may be formed using the sandwich method. A thin layer of matrix crystals is prepared as in the thin-layer method followed by the addition of droplets of aqueous trifluoroacetic acid, the sample and matrix. The sample is then absorbed into the matrix to form the analyte-matrix mixture.

VI. Kits and Devices

Kits

The invention provides a variety of kits for conveniently and/or effectively carrying out methods of the present invention. Typically kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments.

In one aspect, the present invention provides kits comprising the NAV molecules (including any proteins or polynucleotides) of the invention. In one embodiment, the kit comprises one or more functional antigens or function fragments thereof.

The kits can be for protein production, comprising a first polynucleotides comprising a translatable region of an antigen. The kit may further comprise packaging and instructions and/or a delivery agent to form a formulation composition. The delivery agent may comprise a saline, a buffered solution, a lipidoid or any delivery agent disclosed herein.

In one embodiment, the buffer solution may include sodium chloride, calcium chloride, phosphate and/or EDTA. In another embodiment, the buffer solution may include, but is not limited to, saline, saline with 2 mM calcium, 5% sucrose, 5% sucrose with 2 mM calcium, 5% Mannitol, 5% Mannitol with 2 mM calcium, Ringer's lactate, sodium chloride, sodium chloride with 2 mM calcium and mannose (See e.g., U.S. Pub. No. 20120258046; herein incorporated by reference in its entirety). In a futher embodiment, the buffer solutions may be precipitated or it may be lyophilized. The amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations.

The components may also be varied in order to increase the stability of polynucleotides in the buffer solution over a period of time and/or under a variety of conditions.

In one aspect, the present invention provides kits for protein production, comprising: a polynucleotide comprising a translatable region, provided in an amount effective to produce a desired amount of a protein encoded by the translatable region when introduced into a target cell; a second polynucleotide comprising an inhibitory nucleic acid, provided in an amount effective to substantially inhibit the innate immune response of the cell; and packaging and instructions.

In one aspect, the present invention provides kits for protein production, comprising a polynucleotide comprising a translatable region, wherein the polynucleotide exhibits reduced degradation by a cellular nuclease, and packaging and instructions.

In one aspect, the present invention provides kits for protein production, comprising a polynucleotide comprising a translatable region, wherein the polynucleotide exhibits reduced degradation by a cellular nuclease, and a mammalian cell suitable for translation of the translatable region of the first nucleic acid.

Devices

The present invention provides for devices which may incorporate RNAVs comprising polynucleotides that encode polypeptides of interest, e.g., encode antigenic polypeptides. These devices contain in a stable formulation the reagents to synthesize a polynucleotide in a formulation available to be immediately delivered to a subject in need thereof, such as a human patient.

Devices for administration may be employed to deliver the NAVs of the present invention according to single, multi- or split-dosing regimens taught herein. Such devices are taught in, for example, International Application PCT/US2013/30062 filed Mar. 9, 2013, the contents of which are incorporated herein by reference in their entirety.

Method and devices known in the art for multi-administration to cells, organs and tissues are contemplated for use in conjunction with the methods and compositions disclosed herein as embodiments of the present invention. These include, for example, those methods and devices having multiple needles, hybrid devices employing for example lumens or catheters as well as devices utilizing heat, electric current or radiation driven mechanisms.

According to the present invention, these multi-administration devices may be utilized to deliver the single, multi- or split doses contemplated herein. Such devices are taught for example in, International Application PCT/US2013/30062 filed Mar. 9, 2013, the contents of which are incorporated herein by reference in their entirety.

In one embodiment, the NAV is administered subcutaneously or intramuscularly via at least 3 needles to three different, optionally adjacent, sites simultaneously, or within a 60 minutes period (e.g., administration to 4, 5, 6, 7, 8, 9, or 10 sites simultaneously or within a 60 minute period).

Methods and Devices Utilizing Catheters and/or Lumens

Methods and devices using catheters and lumens may be employed to administer the NAVs of the present invention on a single, multi- or split dosing schedule. Such methods and devices are described in International Application PCT/US2013/30062 filed Mar. 9, 2013, the contents of which are incorporated herein by reference in their entirety.

Methods and Devices Utilizing Electrical Current

Methods and devices utilizing electric current may be employed to deliver the NAVs of the present invention according to the single, multi- or split dosing regimens taught herein. Such methods and devices are described in International Application PCT/US2013/30062 filed Mar. 9, 2013, the contents of which are incorporated herein by reference in their entirety.

VII. Definitions

At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C₁₋₆ alkyl” is specifically intended to individually disclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl. Herein a phrase of the form “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g. alkyl) per se is optional.

About: As used herein, the term “about” means +/−10% of the recited value.

Administered in combination: As used herein, the term “administered in combination” or “combined administration” means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient. In some embodiments, they are administered within about 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved.

Adjuvant: As used herein, the term “adjuvant” means a substance that enhances a subject's immune response to an antigen. The NAVs of the present invention may optionally comprise one or more adjuvants.

Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans at any stage of development. In some embodiments, “animal” refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, genetically-engineered animal, or a clone.

Antigen: As defined herein, the term “antigen” or “antibody generator” (“Ag”) refers to a composition, for example, a substance or agent which causes an immune response in an organism, e.g., causes the immune response of the organism to produce antibodies against the substance or agent in particular, which provokes an adaptive immune response in an organism. Antigens can be any immunogenic substance including, in particular, proteins, polypeptides, polysaccharides, nucleic acids, lipids and the like. Exemplary antigens are derived from infectious agents. Such agents can include parts or subunits of infectious agents, for example, coats, coat components, e.g., coat protein or polypeptides, surface components, e.g., surface proteins or polypeptides, capsule components, cell wall components, flagella, fimbrae, and/or toxins or toxoids) of infectious agents, for example, bacteria, viruses, and other microorganisms. Certain antigens, for example, lipids and/or nucleic acids are antigenic, preferably, when combined with proteins and/or polysaccharides.

Antigens of interest or desired antigens: As used herein, the terms “antigens of interest” or “desired antigens” include those proteins and other biomolecules provided herein that are components of or encoded by polynucleotides which are components of one or more NAVs.

Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

Associated with: As used herein, the terms “associated with,” “conjugated,” “linked,” “attached,” and “tethered,” when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An “association” need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization based connectivity sufficiently stable such that the “associated” entities remain physically associated.

Bifunctional: As used herein, the term “bifunctional” refers to any substance, molecule or moiety which is capable of or maintains at least two functions. The functions may effect the same outcome or a different outcome. The structure that produces the function may be the same or different. For example, bifunctional modified RNAs of the present invention may encode a cytotoxic peptide (a first function) while those nucleosides which comprise the encoding RNA are, in and of themselves, cytotoxic (second function). In this example, delivery of the bifunctional modified RNA to a cancer cell would produce not only a peptide or protein molecule which may ameliorate or treat the cancer but would also deliver a cytotoxic payload of nucleosides to the cell should degradation, instead of translation of the modified RNA, occur.

Biocompatible: As used herein, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.

Biodegradable: As used herein, the term “biodegradable” means capable of being broken down into innocuous products by the action of living things.

Biologically active: As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular embodiments, a polynucleotide of the present invention may be considered biologically active if even a portion of the polynucleotides is biologically active or mimics an activity considered biologically relevant.

Cancer stem cells: As used herein, “cancer stem cells” are cells that can undergo self-renewal and/or abnormal proliferation and differentiation to form a tumor.

Chemical terms: The following provides the definition of various chemical terms from “acyl” to “thiol.”

The term “acyl,” as used herein, represents a hydrogen or an alkyl group (e.g., a haloalkyl group), as defined herein, that is attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, butanoyl and the like. Exemplary unsubstituted acyl groups include from 1 to 7, from 1 to 11, or from 1 to 21 carbons. In some embodiments, the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein.

Non-limiting examples of optionally substituted acyl groups include, alkoxycarbonyl, alkoxycarbonylacyl, arylalkoxycarbonyl, aryloyl, carbamoyl, carboxyaldehyde, (heterocyclyl) imino, and (heterocyclyl)oyl:

The “alkoxycarbonyl” group, which as used herein, represents an alkoxy, as defined herein, attached to the parent molecular group through a carbonyl atom (e.g., —C(O)—OR, where R is H or an optionally substituted C₁₋₆, C₁₋₁₀, or C₁₋₂₀ alkyl group). Exemplary unsubstituted alkoxycarbonyl include from 1 to 21 carbons (e.g., from 1 to 11 or from 1 to 7 carbons). In some embodiments, the alkoxy group is further substituted with 1, 2, 3, or 4 substituents as described herein.

The “alkoxycarbonylacyl” group, which as used herein, represents an acyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., —C(O)-alkyl-C(O)—OR, where R is an optionally substituted C₁₋₆, C₁₋₁₀, or C₁₋₂₀ alkyl group). Exemplary unsubstituted alkoxycarbonylacyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C₁₋₆ alkoxycarbonyl-C₁₋₆ acyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ acyl, or C₁₋₂₀ alkoxycarbonyl-C₁₋₂₀ acyl). In some embodiments, each alkoxy and alkyl group is further independently substituted with 1, 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group) for each group.

The “arylalkoxycarbonyl” group, which as used herein, represents an arylalkoxy group, as defined herein, attached to the parent molecular group through a carbonyl (e.g., —C(O)—O-alkyl-aryl). Exemplary unsubstituted arylalkoxy groups include from 8 to 31 carbons (e.g., from 8 to 17 or from 8 to 21 carbons, such as C₆₋₁₀ aryl-C₁₋₆ alkoxy-carbonyl, C₆₋₁₀ aryl-C₁₋₁₀ alkoxy-carbonyl, or C₆₋₁₀ aryl-C₁₋₂₀ alkoxy-carbonyl). In some embodiments, the arylalkoxycarbonyl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

The “aryloyl” group, which as used herein, represents an aryl group, as defined herein, that is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloyl groups are of 7 to 11 carbons. In some embodiments, the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

The “carbamoyl” group, which as used herein, represents —(O)—N(R^(N1))₂, where the meaning of each R^(N1) is found in the definition of “amino” provided herein.

The “carboxyaldehyde” group, which as used herein, represents an acyl group having the structure —CHO.

The “(heterocyclyl) imino” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an imino group. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The “(heterocyclyl)oyl” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through a carbonyl group. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term “alkyl,” as used herein, is inclusive of both straight chain and branched chain saturated groups from 1 to 20 carbons (e.g., from 1 to 10 or from 1 to 6), unless otherwise specified. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C₁₋₆ alkoxy; (2) C₁₋₆ alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., —NH₂) or a substituted amino (i.e., —N(R^(N1))₂, where R^(N1) is as defined for amino); (4) C₆₋₁₀ aryl-C₁₋₆ alkoxy; (5) azido; (6) halo; (7) (C₂₋₉heterocyclyl)oxy; (8) hydroxy, optionally substituted with an O-protecting group; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (11) C₁₋₇ spirocyclyl; (12) thioalkoxy; (13) thiol; (14) —CO₂R^(A′), optionally substituted with an O-protecting group and where R^(A′) is selected from the group consisting of (a) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c) C₆₋₁₀ aryl, (d) hydrogen, (e) C₁₋₆ alk-C₆₋₁₀ aryl, (f) amino-C₁₋₂₀ alkyl, (g) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; (15) —C(O)NR^(B′)R^(C′), where each of R^(B′) and R^(C′) is, independently, selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (16) —SO₂R^(D′), where R^(D′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) C₁₋₆ alk-C₆₋₁₀ aryl, and (d) hydroxy; (17) —SO₂NR^(E′)R^(F′), where each of R^(E′) and R^(F′) is, independently, selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18) —C(O)R^(G′), where R^(G′), is selected from the group consisting of (a) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c) C₆₋₁₀ aryl, (d) hydrogen, (e) C₁₋₆ alk-C₆₋₁₀ aryl, (f) amino-C₁₋₂₀ alkyl, (g) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; (19) —NR^(H′)C(O)R^(I′), wherein R^(H′) is selected from the group consisting of (a1) hydrogen and (b1) C₁₋₆ alkyl, and R^(I′) is selected from the group consisting of (a2) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b2) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c2) C₆₋₁₀ aryl, (d2) hydrogen, (e2) C₁₋₆ alk-C₆₋₁₀ aryl, (f2) amino-C₁₋₂₀ alkyl, (g2) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h2) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; (20) —NR^(J′)C(O)OR^(K′), wherein R^(J′) is selected from the group consisting of (a1) hydrogen and (b1) C₁₋₆ alkyl, and R^(K′) is selected from the group consisting of (a2) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b2) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c2) C₆₋₁₀ aryl, (d2) hydrogen, (e2) C₁₋₆ alk-C₆₋₁₀ aryl, (f2) amino-C₁₋₂₀ alkyl, (g2) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h2) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; and (21) amidine. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C₁-alkaryl can be further substituted with an oxo group to afford the respective aryloyl substituent.

The term “alkylene,” as used herein, represent a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. The term “C_(x-y) alkylene” and the prefix “C_(x-y) alk-” represent alkylene groups having between x and y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C₁₋₆, C₁₋₁₀, C₂₋₂₀, C₂₋₆, C₂₋₁₀, or C₂₋₂₀ alkylene). In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for an alkyl group. Similarly, the suffix “-ene” appended to any group indicates that the group is a divalent group.

Non-limiting examples of optionally substituted alkyl and alkylene groups include acylaminoalkyl, acyloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkylsulfinyl, alkylsulfinylalkyl, aminoalkyl, carbamoylalkyl, carboxyalkyl, carboxyaminoalkyl, haloalkyl, hydroxyalkyl, perfluoroalkyl, and sulfoalkyl:

The “acylaminoalkyl” group, which as used herein, represents an acyl group, as defined herein, attached to an amino group that is in turn attached to the parent molecular group through an alkylene group, as defined herein (i.e., -alkyl-N(R^(N1))—C(O)—R, where R is H or an optionally substituted C₁₋₆, C₁₋₁₀, or C₁₋₂₀ alkyl group (e.g., haloalkyl) and R^(N1) is as defined herein). Exemplary unsubstituted acylaminoalkyl groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21, from 2 to 7, from 2 to 13, from 2 to 21, or from 2 to 41 carbons). In some embodiments, the alkylene group is further substituted with 1, 2, 3, or 4 substituents as described herein, and/or the amino group is —NH₂ or —NHR^(N1), wherein R^(N1) is, independently, OH, NO₂, NH₂, NR^(N2) ₂, SO₂OR^(N2), SO₂R^(N2), SOR^(N2), alkyl, aryl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), or alkoxycarbonylalkyl, and each R^(N2) can be H, alkyl, or aryl.

The “acyloxyalkyl” group, which as used herein, represents an acyl group, as defined herein, attached to an oxygen atom that in turn is attached to the parent molecular group though an alkylene group (i.e., -alkyl-O—C(O)—R, where R is H or an optionally substituted C₁₋₆, C₁₋₁₀, or C₁₋₂₀ alkyl group). Exemplary unsubstituted acyloxyalkyl groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 11 carbons). In some embodiments, the alkylene group is, independently, further substituted with 1, 2, 3, or 4 substituents as described herein.

The “alkoxyalkyl” group, which as used herein, represents an alkyl group that is substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₁₀ alkoxy-C₁₋₁₀ alkyl, or C₁₋₂₀ alkoxy-C₁₋₂₀ alkyl). In some embodiments, the alkyl and the alkoxy each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.

The “alkoxycarbonylalkyl” group, which as used herein, represents an alkyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkyl-C(O)—OR, where R is an optionally substituted C₁₋₂₀, C₁₋₁₀, or C₁₋₆ alkyl group). Exemplary unsubstituted alkoxycarbonylalkyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C₁₋₆ alkoxycarbonyl-C₁₋₆ alkyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ alkyl, or C₁₋₂₀ alkoxycarbonyl-C₁₋₂₀ alkyl). In some embodiments, each alkyl and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).

The “alkylsulfinylalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with an alkylsulfinyl group. Exemplary unsubstituted alkylsulfinylalkyl groups are from 2 to 12, from 2 to 20, or from 2 to 40 carbons. In some embodiments, each alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The “aminoalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with an amino group, as defined herein. The alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO₂R^(A′), where R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl, e.g., carboxy, and/or an N-protecting group).

The “carbamoylalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a carbamoyl group, as defined herein. The alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The “carboxyalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a carboxy group, as defined herein. The alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein, and the carboxy group can be optionally substituted with one or more O-protecting groups.

The “carboxyaminoalkyl” group, which as used herein, represents an aminoalkyl group, as defined herein, substituted with a carboxy, as defined herein. The carboxy, alkyl, and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO₂R^(A′), where R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl, e.g., carboxy, and/or an N-protecting group, and/or an O-protecting group).

The “haloalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or I). A haloalkyl may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens. Haloalkyl groups include perfluoroalkyls (e.g., —CF₃), —CHF₂, —CH₂F, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, and —CHICH₃. In some embodiments, the haloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.

The “hydroxyalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by hydroxymethyl, dihydroxypropyl, and the like. In some embodiments, the hydroxyalkyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.

The “perfluoroalkyl” group, which as used herein, represents an alkyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.

The “sulfoalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a sulfo group of —SO₃H. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein, and the sulfo group can be further substituted with one or more O-protecting groups (e.g., as described herein).

The term “alkenyl,” as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyls include both cis and trans isomers. Alkenyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.

Non-limiting examples of optionally substituted alkenyl groups include, alkoxycarbonylalkenyl, aminoalkenyl, and hydroxyalkenyl:

The “alkoxycarbonylalkenyl” group, which as used herein, represents an alkenyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkenyl-C(O)—OR, where R is an optionally substituted C₁₋₂₀, C₁₋₁₀, or C₁₋₆ alkyl group). Exemplary unsubstituted alkoxycarbonylalkenyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21, or from 4 to 31 carbons, such as C₁₋₆ alkoxycarbonyl-C₂₋₆ alkenyl, C₁₋₁₀ alkoxycarbonyl-C₂₋₁₀ alkenyl, or C₁₋₂₀ alkoxycarbonyl-C₂₋₂₀ alkenyl). In some embodiments, each alkyl, alkenyl, and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).

The “aminoalkenyl” group, which as used herein, represents an alkenyl group, as defined herein, substituted with an amino group, as defined herein. The alkenyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO₂R^(A′), where R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl, e.g., carboxy, and/or an N-protecting group).

The “hydroxyalkenyl” group, which as used herein, represents an alkenyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by dihydroxypropenyl, hydroxyisopentenyl, and the like. In some embodiments, the hydroxyalkenyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.

The term “alkynyl,” as used herein, represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like. Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.

Non-limiting examples of optionally substituted alkynyl groups include alkoxycarbonylalkynyl, aminoalkynyl, and hydroxyalkynyl:

The “alkoxycarbonylalkynyl” group, which as used herein, represents an alkynyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkynyl-C(O)—OR, where R is an optionally substituted C₁₋₂₀, C₁₋₁₀, or C₁₋₆ alkyl group). Exemplary unsubstituted alkoxycarbonylalkynyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21, or from 4 to 31 carbons, such as C₁₋₆ alkoxycarbonyl-C₂₋₆ alkynyl, C₁₋₁₀ alkoxycarbonyl-C₂₋₁₀ alkynyl, or C₁₋₂₀ alkoxycarbonyl-C₂₋₂₀ alkynyl). In some embodiments, each alkyl, alkynyl, and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).

The “aminoalkynyl” group, which as used herein, represents an alkynyl group, as defined herein, substituted with an amino group, as defined herein. The alkynyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO₂R^(A′), where R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl, e.g., carboxy, and/or an N-protecting group).

The “hydroxyalkynyl” group, which as used herein, represents an alkynyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group. In some embodiments, the hydroxyalkynyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.

The term “amino,” as used herein, represents —N(R^(N1))₂, wherein each R^(N1) is, independently, H, OH, NO₂, N(R^(N2))₂, SO₂OR^(N2), SO₂R^(N2), SOR^(N2), an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), heterocyclyl (e.g., heteroaryl), or alkheterocyclyl (e.g., alkheteroaryl), wherein each of these recited R^(N1) groups can be optionally substituted, as defined herein for each group; or two R^(N1) combine to form a heterocyclyl or an N-protecting group, and wherein each R^(N2) is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., —NH₂) or a substituted amino (i.e., —N(R^(N1))₂). In a preferred embodiment, amino is —NH₂ or —NHR^(N1), wherein R^(N1) is, independently, OH, NO₂, NH₂, NR^(N2) ₂, SO₂OR^(N2), SO₂R^(N2), SOR^(N2), alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, and each R^(N2) can be H, C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), or C₆₋₁₀ aryl.

Non-limiting examples of optionally substituted amino groups include acylamino and carbamyl:

The “acylamino” group, which as used herein, represents an acyl group, as defined herein, attached to the parent molecular group though an amino group, as defined herein (i.e., —N(R^(N1))—C(O)—R, where R is H or an optionally substituted C₁₋₆, C₁₋₁₀, or C₁₋₂₀ alkyl group (e.g., haloalkyl) and R^(N1) is as defined herein). Exemplary unsubstituted acylamino groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21, from 2 to 7, from 2 to 13, from 2 to 21, or from 2 to 41 carbons). In some embodiments, the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein, and/or the amino group is —NH₂ or —NHR^(N1), wherein R^(N1) is, independently, OH, NO₂, NH₂, NR^(N2) ₂, SO₂OR^(N2), SO₂R^(N2), SOR^(N2), alkyl, aryl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), or alkoxycarbonylalkyl, and each R^(N2) can be H, alkyl, or aryl.

The “carbamyl” group, which as used herein, refers to a carbamate group having the structure —NR^(N1)C(═O)OR or —OC(═O)N(R^(N1))₂, where the meaning of each R^(N1) is found in the definition of “amino” provided herein, and R is alkyl, cycloalkyl, alkcycloalkyl, aryl, alkaryl, heterocyclyl (e.g., heteroaryl), or alkheterocyclyl (e.g., alkheteroaryl), as defined herein.

The term “amino acid,” as described herein, refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of —O₂H or a sulfo group of —SO₃H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). In some embodiments, the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group. Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine. Amino acid groups may be optionally substituted with one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C₁₋₆ alkoxy; (2) C₁₋₆ alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., —NH₂) or a substituted amino (i.e., —N(R^(N1))₂, where R^(N1) is as defined for amino); (4) C₆₋₁₀ aryl-C₁₋₆ alkoxy; (5) azido; (6) halo; (7) (C₂₋₉ heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (11) C₁₋₇ spirocyclyl; (12) thioalkoxy; (13) thiol; (14) —CO₂R^(A′), where R^(A′) is selected from the group consisting of (a) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c) C₆₋₁₀ aryl, (d) hydrogen, (e) C₁₋₆ alk-C₆₋₁₀ aryl, (f) amino-C₁₋₂₀ alkyl, (g) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; (15) —C(O)NR^(B′)R^(C′), where each of R^(B′) and R^(C′) is, independently, selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (16) —SO₂R^(D′), where R^(D′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) C₁₋₆ alk-C₆₋₁₀ aryl, and (d) hydroxy; (17) —SO₂NR^(E′)R^(F′), where each of R^(E′) and R^(F′) is, independently, selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18) —C(O)R^(G′), where R^(G′), is selected from the group consisting of (a) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c) C₆₋₁₀ aryl, (d) hydrogen, (e) C₁₋₆ alk-C₆₋₁₀ aryl, (f) amino-C₁₋₂₀ alkyl, (g) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; (19) —NR^(H′)C(O)R^(I′), wherein R^(H′) is selected from the group consisting of (a1) hydrogen and (b1) C₁₋₆ alkyl, and R^(I′) is selected from the group consisting of (a2) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b2) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c2) C₆₋₁₀ aryl, (d2) hydrogen, (e2) C₁₋₆ alk-C₆₋₁₀ aryl, (f2) amino-C₁₋₂₀ alkyl, (g2) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h2) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; (20) —NR^(J′)C(O)OR^(K′), wherein R^(J′) is selected from the group consisting of (a1) hydrogen and (b1) C₁₋₆ alkyl, and R^(K′) is selected from the group consisting of (a2) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl), (b2) C₂₋₂₀ alkenyl (e.g., C₂₋₆ alkenyl), (c2) C₆₋₁₀ aryl, (d2) hydrogen, (e2) C₁₋₆ alk-C₆₋₁₀ aryl, (f2) amino-C₁₋₂₀ alkyl, (g2) polyethylene glycol of —(CH₂)_(s2)(OCH₂CH₂)_(s1)(CH₂)_(s3)OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C₁₋₂₀ alkyl, and (h2) amino-polyethylene glycol of —NR^(N1)(CH₂)_(s2)(CH₂CH₂O)_(s1)(CH₂)_(s3)NR^(N1), wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R^(N1) is, independently, hydrogen or optionally substituted C₁₋₆ alkyl; and (21) amidine. In some embodiments, each of these groups can be further substituted as described herein.

The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, indenyl, and the like, and may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: (1) C₁₋₇ acyl (e.g., carboxyaldehyde); (2) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkylsulfinyl-C₁₋₆ alkyl, amino-C₁₋₆ alkyl, azido-C₁₋₆ alkyl, (carboxyaldehyde)-C₁₋₆ alkyl, halo-C₁₋₆ alkyl (e.g., perfluoroalkyl), hydroxy-C₁₋₆ alkyl, nitro-C₁₋₆ alkyl, or C₁₋₆ thioalkoxy-C₁₋₆ alkyl); (3) C₁₋₂₀ alkoxy (e.g., C₁₋₆ alkoxy, such as perfluoroalkoxy); (4) C₁₋₆ alkylsulfinyl; (5) C₆₋₁₀ aryl; (6) amino; (7) C₁₋₆ alk-C₆₋₁₀ aryl; (8) azido; (9) C₃₋₈ cycloalkyl; (10) C₁₋₆ alk-C₃₋₈ cycloalkyl; (11) halo; (12) C₁₋₁₂ heterocyclyl (e.g., C₁₋₁₂ heteroaryl); (13) (C₁₋₁₂ heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) C₁₋₂₀ thioalkoxy (e.g., C₁₋₆ thioalkoxy); (17) —(CH₂)_(q)CO₂R^(A′), where q is an integer from zero to four, and R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18) —(CH₂)_(q)CONR^(B′)R^(C′), where q is an integer from zero to four and where R^(B′) and R^(C′) are independently selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (19) —(CH₂)_(q)SO₂R^(D′), where q is an integer from zero to four and where R^(D′) is selected from the group consisting of (a) alkyl, (b) C₆₋₁₀ aryl, and (c) alk-C₆₋₁₀ aryl; (20) —(CH₂)_(q)SO₂NR^(E′)R^(F′), where q is an integer from zero to four and where each of R^(E′) and R^(F′) is, independently, selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (21) thiol; (22) C₆₋₁₀ aryloxy; (23) C₃₋₈ cycloalkoxy; (24) C₆₋₁₀ aryl-C₁₋₆ alkoxy; (25) C₁₋₆ alk-C₁₋₁₂ heterocyclyl (e.g., C₁₋₆ alk-C₁₋₁₂ heteroaryl); (26) C₂₋₂₀ alkenyl; and (27) C₂₋₂₀ alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C₁-alkaryl or a C₁-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.

The “arylalkyl” group, which as used herein, represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C₁₋₆ alk-C₆₋₁₀ aryl, C₁₋₁₀ alk-C₆₋₁₀ aryl, or C₁₋₂₀ alk-C₆₋₁₀ aryl). In some embodiments, the alkylene and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. Other groups preceded by the prefix “alk-” are defined in the same manner, where “alk” refers to a C₁₋₆ alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.

The term “azido” represents an —N₃ group, which can also be represented as —N═N═N.

The term “bicyclic,” as used herein, refer to a structure having two rings, which may be aromatic or non-aromatic. Bicyclic structures include spirocyclyl groups, as defined herein, and two rings that share one or more bridges, where such bridges can include one atom or a chain including two, three, or more atoms. Exemplary bicyclic groups include a bicyclic carbocyclyl group, where the first and second rings are carbocyclyl groups, as defined herein; a bicyclic aryl groups, where the first and second rings are aryl groups, as defined herein; bicyclic heterocyclyl groups, where the first ring is a heterocyclyl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group; and bicyclic heteroaryl groups, where the first ring is a heteroaryl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group. In some embodiments, the bicyclic group can be substituted with 1, 2, 3, or 4 substituents as defined herein for cycloalkyl, heterocyclyl, and aryl groups.

The term “boranyl,” as used herein, represents —B(R^(B1))₃, where each R^(B1) is, independently, selected from the group consisting of H and optionally substituted alkyl. In some embodiments, the boranyl group can be substituted with 1, 2, 3, or 4 substituents as defined herein for alkyl.

The terms “carbocyclic” and “carbocyclyl,” as used herein, refer to an optionally substituted C₃₋₁₂ monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl groups.

The term “carbonyl,” as used herein, represents a C(O) group, which can also be represented as C═O.

The term “carboxy,” as used herein, means —O₂H.

The term “cyano,” as used herein, represents an —N group.

The term “cycloalkyl,” as used herein represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycle heptyl, and the like. When what would otherwise be a cycloalkyl group includes one or more carbon-carbon double bonds, the group is referred to as a “cycloalkenyl” group. For the purposes of this invention, cycloalkenyl excludes aryl groups. When what would otherwise be a cycloalkyl group includes one or more carbon-carbon triple bonds, the group is referred to as a “cycloalkynyl” group. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, and the like. The cycloalkyl groups of this invention can be optionally substituted with: (1) C₁₋₇ acyl (e.g., carboxyaldehyde); (2) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkylsulfinyl-C₁₋₆ alkyl, amino-C₁₋₆ alkyl, azido-C₁₋₆ alkyl, (carboxyaldehyde)-C₁₋₆ alkyl, halo-C₁₋₆ alkyl (e.g., perfluoroalkyl), hydroxy-C₁₋₆ alkyl, nitro-C₁₋₆ alkyl, or C₁₋₆ thioalkoxy-C₁₋₆ alkyl); (3) C₁₋₂₀ alkoxy (e.g., C₁₋₆ alkoxy, such as perfluoroalkoxy); (4) C₁₋₆ alkylsulfinyl; (5) C₆₋₁₀ aryl; (6) amino; (7) C₁₋₆ alk-C₆₋₁₀ aryl; (8) azido; (9) C₃₋₈ cycloalkyl; (10) C₁₋₆ alk-C₃₋₈ cycloalkyl; (11) halo; (12) C₁₋₁₂ heterocyclyl (e.g., C₁₋₁₂ heteroaryl); (13) (C₁₋₁₂ heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) C₁₋₂₀ thioalkoxy (e.g., C₁₋₆ thioalkoxy); (17) —(CH₂)_(q)CO₂R^(A′), where q is an integer from zero to four, and R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18) —(CH₂)_(q)CONR^(B′)R^(C′), where q is an integer from zero to four and where R^(B′) and R^(C′) are independently selected from the group consisting of (a) hydrogen, (b) C₆₋₁₀ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (19) —(CH₂)_(q)SO₂R^(D′), where q is an integer from zero to four and where R^(D′) is selected from the group consisting of (a) C₆₋₁₀ alkyl, (b) C₆₋₁₀ aryl, and (c) C₁₋₆ alk-C₆₋₁₀ aryl; (20) —(CH₂)_(q)SO₂NR^(E′)R^(F′), where q is an integer from zero to four and where each of R^(E′) and R^(F′) is, independently, selected from the group consisting of (a) hydrogen, (b) C₆₋₁₀ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (21) thiol; (22) C₆₋₁₀ aryloxy; (23) C₃₋₈ cycloalkoxy; (24) C₆₋₁₀ aryl-C₁₋₆ alkoxy; (25) C₁₋₆ alk-C₁₋₁₂heterocyclyl (e.g., C₁₋₆ alk-C₁₋₁₂heteroaryl); (26) oxo; (27) C₂₋₂₀ alkenyl; and (28) C₂₋₂₀ alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C₁-alkaryl or a C₁-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.

The “cycloalkylalkyl” group, which as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein (e.g., an alkylene group of from 1 to 4, from 1 to 6, from 1 to 10, or form 1 to 20 carbons). In some embodiments, the alkylene and the cycloalkyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.

The term “halo,” as used herein, represents a halogen selected from bromine, chlorine, iodine, or fluorine.

The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. The terms “heteroalkenyl” and heteroalkynyl,” as used herein refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl and heteroalkynyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.

Non-limiting examples of optionally substituted heteroalkyl, heteroalkenyl, and heteroalkynyl groups include acyloxy, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonylalkoxy, alkynyloxy, aminoalkoxy, arylalkoxy, carboxyalkoxy, cycloalkoxy, haloalkoxy, (heterocyclyl)oxy, perfluoroalkoxy, thioalkoxy, and thioheterocyclylalkyl:

The “acyloxy” group, which as used herein, represents an acyl group, as defined herein, attached to the parent molecular group though an oxygen atom (i.e., —O—C(O)—R, where R is H or an optionally substituted C₁₋₆, C₁₋₁₀, or C₁₋₂₀ alkyl group). Exemplary unsubstituted acyloxy groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 11 carbons). In some embodiments, the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein.

The “alkenyloxy” group, which as used here, represents a chemical substituent of formula —OR, where R is a C₂₋₂₀ alkenyl group (e.g., C₂₋₆ or C₂₋₁₀ alkenyl), unless otherwise specified. Exemplary alkenyloxy groups include ethenyloxy, propenyloxy, and the like. In some embodiments, the alkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).

The “alkoxy” group, which as used herein, represents a chemical substituent of formula —OR, where R is a C₁₋₂₀ alkyl group (e.g., C₁₋₆ or C₁₋₁₀ alkyl), unless otherwise specified. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., hydroxy or alkoxy).

The “alkoxyalkoxy” group, which as used herein, represents an alkoxy group that is substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkoxy groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C₁₋₆ alkoxy-C₁₋₆ alkoxy, C₁₋₁₀ alkoxy-C₁₋₁₀ alkoxy, or C₁₋₂₀ alkoxy-C₁₋₂₀ alkoxy). In some embodiments, the each alkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The “alkoxycarbonylalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., —O-alkyl-C(O)—OR, where R is an optionally substituted C₁₋₆, C₁₋₁₀, or C₁₋₂₀ alkyl group). Exemplary unsubstituted alkoxycarbonylalkoxy include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C₁₋₆ alkoxycarbonyl-C₁₋₆ alkoxy, C₁₋₁₀ alkoxycarbonyl-C₁₋₁₀ alkoxy, or C₁₋₂₀ alkoxycarbonyl-C₁₋₂₀ alkoxy). In some embodiments, each alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group).

The “alkynyloxy” group, which as used herein, represents a chemical substituent of formula —OR, where R is a C₂₋₂₀ alkynyl group (e.g., C₂₋₆ or C₂₋₁₀ alkynyl), unless otherwise specified. Exemplary alkynyloxy groups include ethynyloxy, propynyloxy, and the like. In some embodiments, the alkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).

The “aminoalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, substituted with an amino group, as defined herein. The alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO₂R^(A′), where R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl, e.g., carboxy).

The “arylalkoxy” group, which as used herein, represents an alkaryl group, as defined herein, attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted arylalkoxy groups include from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C₆₋₁₀ aryl-C₁₋₆ alkoxy, C₆₋₁₀ aryl-C₁₋₁₀ alkoxy, or C₆₋₁₀ aryl-C₁₋₂₀ alkoxy). In some embodiments, the arylalkoxy group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

The “aryloxy” group, which as used herein, represents a chemical substituent of formula —OR′, where R′ is an aryl group of 6 to 18 carbons, unless otherwise specified. In some embodiments, the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

The “carboxyalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, substituted with a carboxy group, as defined herein. The alkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the alkyl group, and the carboxy group can be optionally substituted with one or more O-protecting groups.

The “cycloalkoxy” group, which as used herein, represents a chemical substituent of formula —OR, where R is a C₃₋₈ cycloalkyl group, as defined herein, unless otherwise specified. The cycloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein. Exemplary unsubstituted cycloalkoxy groups are from 3 to 8 carbons. In some embodiment, the cycloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The “haloalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or I). A haloalkoxy may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens. Haloalkoxy groups include perfluoroalkoxys (e.g., —OCF₃), —OCHF₂, —OCH₂F, —OCCl₃, —OCH₂CH₂Br, —OCH₂CH(CH₂CH₂Br)CH₃, and —OCHICH₃. In some embodiments, the haloalkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.

The “(heterocyclyl)oxy” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an oxygen atom. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The “perfluoroalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, where each hydrogen radical bound to the alkoxy group has been replaced by a fluoride radical. Perfluoroalkoxy groups are exemplified by trifluoromethoxy, pentafluoroethoxy, and the like.

The “alkylsulfinyl” group, which as used herein, represents an alkyl group attached to the parent molecular group through an —S(O)— group. Exemplary unsubstituted alkylsulfinyl groups are from 1 to 6, from 1 to 10, or from 1 to 20 carbons. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

The “thioarylalkyl” group, which as used herein, represents a chemical substituent of formula —SR, where R is an arylalkyl group. In some embodiments, the arylalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The “thioalkoxy” group as used herein, represents a chemical substituent of formula —SR, where R is an alkyl group, as defined herein. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The “thioheterocyclylalkyl” group, which as used herein, represents a chemical substituent of formula —SR, where R is an heterocyclylalkyl group. In some embodiments, the heterocyclylalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.

The term “heteroaryl,” as used herein, represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system. Exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. In some embodiment, the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups as defined for a heterocyclyl group.

The term “heteroarylalkyl” refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted heteroarylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C₁₋₆ alk-C₁₋₁₂ heteroaryl, C₁₋₁₀ alk-C₁₋₁₂ heteroaryl, or C₁₋₂₀ alk-C₁₋₁₂ heteroaryl). In some embodiments, the alkylene and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group. Heteroarylalkyl groups are a subset of heterocyclylalkyl groups.

The term “heterocyclyl,” as used herein represents a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

The 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclyl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Examples of fused heterocyclyls include tropanes and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiadiazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl), purinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl), tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, dihydroquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, and the like, including dihydro and tetrahydro forms thereof, where one or more double bonds are reduced and replaced with hydrogens. Still other exemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl (e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl); 2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g., 2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl); 4,5-dihydro-5-oxo-1H-triazolyl (e.g., 4,5-dihydro-3-methyl-4-amino 5-oxo-1H-triazolyl); 1,2,3,4-tetrahydro-2,4-dioxopyridinyl (e.g., 1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridinyl); 2,6-dioxo-piperidinyl (e.g., 2,6-dioxo-3-ethyl-3-phenylpiperidinyl); 1,6-dihydro-6-oxopyridiminyl; 1,6-dihydro-4-oxopyrimidinyl (e.g., 2-(methylthio)-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl); 1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (e.g., 1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl); 1,6-dihydro-6-oxo-pyridazinyl (e.g., 1,6-dihydro-6-oxo-3-ethylpyridazinyl); 1,6-dihydro-6-oxo-1,2,4-triazinyl (e.g., 1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazinyl); 2,3-dihydro-2-oxo-1H-indolyl (e.g., 3,3-dimethyl-2,3-dihydro-2-oxo-1H-indolyl and 2,3-dihydro-2-oxo-3,3′-spiropropane-1H-indol-1-yl); 1,3-dihydro-1-oxo-2H-iso-indolyl; 1,3-dihydro-1,3-dioxo-2H-iso-indolyl; 1H-benzopyrazolyl (e.g., 1-(ethoxycarbonyl)-1H-benzopyrazolyl); 2,3-dihydro-2-oxo-1H-benzimidazolyl (e.g., 3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolyl); 2,3-dihydro-2-oxo-benzoxazolyl (e.g., 5-chloro-2,3-dihydro-2-oxo-benzoxazolyl); 2,3-dihydro-2-oxo-benzoxazolyl; 2-oxo-2H-benzopyranyl; 1,4-benzodioxanyl; 1,3-benzodioxanyl; 2,3-dihydro-3-oxo,4H-1,3-benzothiazinyl; 3,4-dihydro-4-oxo-3H-quinazolinyl (e.g., 2-methyl-3,4-dihydro-4-oxo-3H-quinazolinyl); 1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl (e.g., 1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl); 1,2,3,6-tetrahydro-2,6-dioxo-7H-purinyl (e.g., 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purinyl); 1,2,3,6-tetrahydro-2,6-dioxo-1H-purinyl (e.g., 1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purinyl); 2-oxobenz[c, d]indolyl; 1,1-dioxo-2H-naphth[1,8-c, d] isothiazolyl; and 1,8-naphthylenedicarboxamido. Additional heterocyclics include 3,3a,4,5,6,6a-hexahydro-pyrrolo[3,4-b]pyrrol-(2H)-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, homopiperazinyl (or diazepanyl), tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, and thiocanyl. Heterocyclic groups also include groups of the formula

where

E′ is selected from the group consisting of —N— and —CH—; F′ is selected from the group consisting of —N═CH—, —NH—CH₂—, —NH—C(O)—, —NH—, —CH═N—, —CH₂—NH—, —C(O)—NH—, —CH═CH—, —CH₂—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —O—, and —S—; and G′ is selected from the group consisting of —CH— and —N—. Any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) C₁₋₇ acyl (e.g., carboxyaldehyde); (2) C₁₋₂₀ alkyl (e.g., C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkylsulfinyl-C₁₋₆ alkyl, amino-C₁₋₆ alkyl, azido-C₁₋₆ alkyl, (carboxyaldehyde)-C₁₋₆ alkyl, halo-C₁₋₆ alkyl (e.g., perfluoroalkyl), hydroxy-C₁₋₆ alkyl, nitro-C₁₋₆ alkyl, or C₁₋₆ thioalkoxy-C₁₋₆ alkyl); (3) C₁₋₂₀ alkoxy (e.g., C₁₋₆ alkoxy, such as perfluoroalkoxy); (4) C₁₋₆ alkylsulfinyl; (5) C₆₋₁₀ aryl; (6) amino; (7) C₁₋₆ alk-C₆₋₁₀ aryl; (8) azido; (9) C₃₋₈ cycloalkyl; (10) C₁₋₆ alk-C₃₋₈ cycloalkyl; (11) halo; (12) C₁₋₁₂ heterocyclyl (e.g., C₂₋₁₂ heteroaryl); (13) (C₁₋₁₂ heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) C₁₋₂₀ thioalkoxy (e.g., C₁₋₆ thioalkoxy); (17) —(CH₂)_(q)CO₂R^(A′), where q is an integer from zero to four, and R^(A′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18) —(CH₂)_(q)CONR^(B′)R^(C′), where q is an integer from zero to four and where R^(B′) and R^(C′) are independently selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (19) —(CH₂)_(q)SO₂R^(D′), where q is an integer from zero to four and where R^(D′) is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, and (c) C₁₋₆ alk-C₆₋₁₀ aryl; (20) —(CH₂)_(q)SO₂NR^(E′)R^(F′), where q is an integer from zero to four and where each of R^(E′) and R^(F′) is, independently, selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (21) thiol; (22) C₆₋₁₀ aryloxy; (23) C₃₋₈ cycloalkoxy; (24) arylalkoxy; (25) C₁₋₆ alk-C₁₋₁₂ heterocyclyl (e.g., C₁₋₆ alk-C₁₋₁₂ heteroaryl); (26) oxo; (27) (C₁₋₁₂ heterocyclyl)imino; (28) C₂₋₂₀ alkenyl; and (29) C₂₋₂₀ alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C₁-alkaryl or a C₁-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.

The “heterocyclylalkyl” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted heterocyclylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C₁₋₆ alk-C₁₋₁₂ heterocyclyl, C₁₋₁₀ alk-C₁₋₁₂ heterocyclyl, or C₁₋₂₀ alk-C₁₋₁₂ heterocyclyl). In some embodiments, the alkylene and the heterocyclyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group. The term “hydrocarbon,” as used herein, represents a group consisting only of carbon and hydrogen atoms.

The term “hydroxy,” as used herein, represents an —OH group.

The term “N-protected amino,” as used herein, refers to an amino group, as defined herein, to which is attached one or two N-protecting groups, as defined herein.

The term “N-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3^(rd) Edition (John Wiley & Sons, N.Y., 1999), which is incorporated herein by reference. N-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, alkaryl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like and silyl groups, such as trimethylsilyl, and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

The term “nitro,” as used herein, represents an —NO₂ group.

The term “O-protecting group,” as used herein, represents those groups intended to protect an oxygen containing (e.g., phenol, hydroxyl, or carbonyl) group against undesirable reactions during synthetic procedures. Commonly used O-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3^(rd) Edition (John Wiley & Sons, N.Y., 1999), which is incorporated herein by reference. Exemplary O-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl; alkylcarbonyl groups, such as acyl, acetyl, propionyl, pivaloyl, and the like; optionally substituted arylcarbonyl groups, such as benzoyl; silyl groups, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), triisopropylsilyl (TIPS), and the like; ether-forming groups with the hydroxyl, such methyl, methoxymethyl, tetrahydropyranyl, benzyl, p-methoxybenzyl, trityl, and the like; alkoxycarbonyls, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-isopropoxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl, 2-ethylhexyloxycarbonyl, cyclohexyloxycarbonyl, methyloxycarbonyl, and the like; alkoxyalkoxycarbonyl groups, such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-butoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, 2-butenoxycarbonyl, 3-methyl-2-butenoxycarbonyl, and the like; haloalkoxycarbonyls, such as 2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and the like; optionally substituted arylalkoxycarbonyl groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, fluorenylmethyloxycarbonyl, and the like; and optionally substituted aryloxycarbonyl groups, such as phenoxycarbonyl, p-nitrophenoxycarbonyl, o-nitrophenoxycarbonyl, 2,4-dinitrophenoxycarbonyl, p-methyl-phenoxycarbonyl, m-methylphenoxycarbonyl, o-bromophenoxycarbonyl, 3,5-dimethylphenoxycarbonyl, p-chlorophenoxycarbonyl, 2-chloro-4-nitrophenoxy-carbonyl, and the like); substituted alkyl, aryl, and alkaryl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenymethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl); carbonyl-protecting groups (e.g., acetal and ketal groups, such as dimethyl acetal, 1,3-dioxolane, and the like; acylal groups; and dithiane groups, such as 1,3-dithianes, 1,3-dithiolane, and the like); carboxylic acid-protecting groups (e.g., ester groups, such as methyl ester, benzyl ester, t-butyl ester, orthoesters, and the like; and oxazoline groups.

The term “oxo” as used herein, represents ═O.

The prefix “perfluoro,” as used herein, represents anyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. For example, perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.

The term “protected hydroxyl,” as used herein, refers to an oxygen atom bound to an O-protecting group.

The term “spirocyclyl,” as used herein, represents a C₂₋₇ alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group, and also a C₁₋₆ heteroalkylene diradical, both ends of which are bonded to the same atom. The heteroalkylene radical forming the spirocyclyl group can containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the spirocyclyl group includes one to seven carbons, excluding the carbon atom to which the diradical is attached. The spirocyclyl groups of the invention may be optionally substituted with 1, 2, 3, or 4 substituents provided herein as optional substituents for cycloalkyl and/or heterocyclyl groups.

The term “sulfonyl,” as used herein, represents an —S(O)₂— group.

The term “thiol,” as used herein represents an —SH group.

Chimera: As used herein, “chimera” is an entity having two or more incongruous or heterogeneous parts or regions.

Chimeric polynucleotide: As used herein, “chimeric polynucleotides” are those nucleic acid polymers having portions or regions which differ in size and/or chemical modification pattern, chemical modification position, chemical modification percent or chemical modification population and combinations of the foregoing.

Compound: As used herein, the term “compound,” is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone—enol pairs, amide—imidic acid pairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.

The compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.

Conserved: As used herein, the term “conserved” refers to nucleotides or amino acid residues of a polynucleotide sequence or polypeptide sequence, respectively, that are those that occur unaltered in the same position of two or more sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences.

In some embodiments, two or more sequences are said to be “completely conserved” if they are 100% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are about 70% identical, about 80% identical, about 90% identical, about 95%, about 98%, or about 99% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. Conservation of sequence may apply to the entire length of an polynucleotide or polypeptide or may apply to a portion, region or feature thereof.

Controlled Release: As used herein, the term “controlled release” refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome.

Cyclic or Cyclized: As used herein, the term “cyclic” refers to the presence of a continuous loop. Cyclic molecules need not be circular, only joined to form an unbroken chain of subunits. Cyclic molecules such as the engineered RNA or mRNA of the present invention may be single units or multimers or comprise one or more components of a complex or higher order structure.

Cytostatic: As used herein, “cytostatic” refers to inhibiting, reducing, suppressing the growth, division, or multiplication of a cell (e.g., a mammalian cell (e.g., a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.

Cytotoxic: As used herein, “cytotoxic” refers to killing or causing injurious, toxic, or deadly effect on a cell (e.g., a mammalian cell (e.g., a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.

Delivery: As used herein, “delivery” refers to the act or manner of delivering a compound, substance, entity, moiety, cargo or payload.

Delivery Agent: As used herein, “delivery agent” refers to any substance which facilitates, at least in part, the in vivo delivery of a polynucleotide to targeted cells.

Destabilized: As used herein, the term “destable,” “destabilize,” or “destabilizing region” means a region or molecule that is less stable than a starting, wild-type or native form of the same region or molecule.

Detectable label: As used herein, “detectable label” refers to one or more markers, signals, or moieties which are attached, incorporated or associated with another entity that is readily detected by methods known in the art including radiography, fluorescence, chemiluminescence, enzymatic activity, absorbance and the like. Detectable labels include radioisotopes, fluorophores, chromophores, enzymes, dyes, metal ions, ligands such as biotin, avidin, streptavidin and haptens, quantum dots, and the like. Detectable labels may be located at any position in the peptides or proteins disclosed herein. They may be within the amino acids, the peptides, or proteins, or located at the N- or C-termini.

Diastereomer: As used herein, the term “diastereomer,” means stereoisomers that are not mirror images of one another and are non-superimposable on one another.

Digest: As used herein, the term “digest” means to break apart into smaller pieces or components. When referring to polypeptides or proteins, digestion results in the production of peptides.

Differentiated cell: As used herein, the term “differentiated cell” refers to any somatic cell that is not, in its native form, pluripotent. Differentiated cell also encompasses cells that are partially differentiated.

Differentiation: As used herein, the term “differentiation factor” refers to a developmental potential altering factor such as a protein, RNA or small molecule that can induce a cell to differentiate to a desired cell-type.

Differentiate: As used herein, “differentiate” refers to the process where an uncommitted or less committed cell acquires the features of a committed cell.

Distal: As used herein, the term “distal” means situated away from the center or away from a point or region of interest.

Dosing regimen: As used herein, a “dosing regimen” is a schedule of administration or physician determined regimen of treatment, prophylaxis, or palliative care.

Dose splitting factor (DSF)-ratio of PUD of dose split treatment divided by PUD of total daily dose or single unit dose. The value is derived from comparison of dosing regimens groups.

Enantiomer: As used herein, the term “enantiomer” means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

Encapsulate: As used herein, the term “encapsulate” means to enclose, surround or encase.

Encoded protein cleavage signal: As used herein, “encoded protein cleavage signal” refers to the nucleotide sequence which encodes a protein cleavage signal.

Engineered: As used herein, embodiments of the invention are “engineered” when they are designed to have a feature or property, whether structural or chemical, that varies from a starting point, wild type or native molecule.

Effective Amount: As used herein, the term “effective amount” of an agentis that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied. For example, in the context of administering an agent that treats cancer, an effective amount of an agent is, for example, an amount sufficient to achieve treatment, as defined herein, of cancer, as compared to the response obtained without administration of the agent.

Exosome: As used herein, “exosome” is a vesicle secreted by mammalian cells or a complex involved in RNA degradation.

Expression: As used herein, “expression” of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5′ cap formation, and/or 3′ end processing); (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.

Feature: As used herein, a “feature” refers to a characteristic, a property, or a distinctive element.

Formulation: As used herein, a “formulation” includes at least a polynucleotide of a NAV and a delivery agent.

Fragment: A “fragment,” as used herein, refers to a portion. For example, fragments of proteins may comprise polypeptides obtained by digesting full-length protein isolated from cultured cells.

Functional: As used herein, a “functional” biological molecule is a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.

Homology: As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g. between nucleic acid molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term “homologous” necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). In accordance with the invention, two polynucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50%, 60%, 70%, 80%, 90%, 95%, or even 99% for at least one stretch of at least about 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. In accordance with the invention, two protein sequences are considered to be homologous if the proteins are at least about 50%, 60%, 70%, 80%, or 90% identical for at least one stretch of at least about 20 amino acids.

Identity: As used herein, the term “identity” refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules.

Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, N.Y., 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, N.Y., 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, N.J., 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, N.Y., 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990)).

Infectious Agent: As used herein, the phrase “infectious agent” means an agent capable of producing an infection in an organism, for example, in an animal. An infectious agent may refer to any microorganism, virus, infectious substance, or biological product that may be engineered as a result of biotechnology, or any naturally occurring or bioengineered component of any such microorganism, virus, infectious substance, or biological product, can cause emerging and contagious disease, death or other biological malfunction in a human, an animal, a plant or another living organism.

Inhibit expression of a gene: As used herein, the phrase “inhibit expression of a gene” means to cause a reduction in the amount of an expression product of the gene. The expression product can be an RNA transcribed from the gene (e.g., an mRNA) or a polypeptide translated from an mRNA transcribed from the gene. Typically a reduction in the level of an mRNA results in a reduction in the level of a polypeptide translated therefrom. The level of expression may be determined using standard techniques for measuring mRNA or protein.

Influenza: As used herein, “influenza” or “flu” is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae, the influenza viruses.

Isomer: As used herein, the term “isomer” means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (−)) or cis/trans isomers). According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).

In vivo: As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).

Isolated: As used herein, the term “isolated” refers to a substance or entity that has been separated from at least some of the components with which it was associated (whether in nature or in an experimental setting). Isolated substances may have varying levels of purity in reference to the substances from which they have been associated. Isolated substances and/or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated agents are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components. Substantially isolated: By “substantially isolated” is meant that the compound is substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present disclosure. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present disclosure, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

IVT Polynucleotide: As used herein, an “IVT polynucleotide” is a linear polynucleotide which may be made using in vitro transcription (IVT) enzymatic synthesis methods.

Linker: As used herein, a “linker” refers to a group of atoms, e.g., 10-1,000 atoms, and can be comprised of the atoms or groups such as, but not limited to, carbon, amino, alkylamino, oxygen, sulfur, sulfoxide, sulfonyl, carbonyl, and imine. The linker can be attached to a modified nucleoside or nucleotide on the nucleobase or sugar moiety at a first end, and to a payload, e.g., a detectable or therapeutic agent, at a second end. The linker may be of sufficient length as to not interfere with incorporation into a nucleic acid sequence. The linker can be used for any useful purpose, such as to form polynucleotide multimers (e.g., through linkage of two or more chimeric polynucleotides molecules or IVT polynucleoties) or polynucleotides conjugates, as well as to administer a payload, as described herein. Examples of chemical groups that can be incorporated into the linker include, but are not limited to, alkyl, alkenyl, alkynyl, amido, amino, ether, thioether, ester, alkylene, heteroalkylene, aryl, or heterocyclyl, each of which can be optionally substituted, as described herein. Examples of linkers include, but are not limited to, unsaturated alkanes, polyethylene glycols (e.g., ethylene or propylene glycol monomeric units, e.g., diethylene glycol, dipropylene glycol, triethylene glycol, tripropylene glycol, tetraethylene glycol, or tetraethylene glycol), and dextran polymers and derivatives thereof. Other examples include, but are not limited to, cleavable moieties within the linker, such as, for example, a disulfide bond (—S—S—) or an azo bond (—N═N—), which can be cleaved using a reducing agent or photolysis. Non-limiting examples of a selectively cleavable bond include an amido bond can be cleaved for example by the use of tris(2-carboxyethyl)phosphine (TCEP), or other reducing agents, and/or photolysis, as well as an ester bond can be cleaved for example by acidic or basic hydrolysis.

MicroRNA (miRNA) binding site: As used herein, a microRNA (miRNA) binding site represents a nucleotide location or region of a nucleic acid transcript to which at least the “seed” region of a miRNA binds.

Modified: As used herein “modified” refers to a changed state or structure of a molecule of the invention. Molecules may be modified in many ways including chemically, structurally, and functionally. In one embodiment, the polynucleotide molecules of the present invention are modified by the introduction of non-natural nucleosides and/or nucleotides, e.g., as it relates to the natural ribonucleotides A, U, G, and C. Noncanonical nucleotides such as the cap structures are not considered “modified” although they differ from the chemical structure of the A, C, G, U ribonucleotides.

Mucus: As used herein, “mucus” refers to the natural substance that is viscous and comprises mucin glycoproteins.

Naturally occurring: As used herein, “naturally occurring” means existing in nature without artificial aid.

Neutralizing antibody: As used herein, a “neutralizing antibody” refers to an antibody which binds to its antigen and defends a cell from an antigen or infectious agent by neutralizing or abolishing any biological activity it has.

Non-human vertebrate: As used herein, a “non human vertebrate” includes all vertebrates except Homo sapiens, including wild and domesticated species. Examples of non-human vertebrates include, but are not limited to, mammals, such as alpaca, banteng, bison, camel, cat, cattle, deer, dog, donkey, gayal, goat, guinea pig, horse, llama, mule, pig, rabbit, reindeer, sheep water buffalo, and yak.

Nucleic Acid Vaccine: As used herein, “nucleic acid vaccine” or “NAV” or “NAV composition” refers to a vaccine or vaccine composition which includes a nucleic acid or nucleic acid molecule (e.g., a polynucleotide) encoding an antigen (e.g., an antigenic protein or polypeptide.) In exemplary embodiments, a nucleic acid vaccine or NAV includes a ribonucleic (“RNA”) polynucleotide, ribonucleic acid (“RNA”) or ribonucleic acid (“RNA”) molecule. Such embodiments can be referred to as ribonucleic acid (“RNA”) vaccines (RNAVs). In preferred embodiments, a nucleic acid vaccine or NAV includes a messenger RNA (“mRNA”) polynucleotide, messenger RNA (“mRNA”) or messenger RNA (“mRNA”) molecule as described in detail herein. Such embodiments can be referred to as messenger RNA (“mRNA”) vaccines (mRNAVs).

Off-target: As used herein, “off target” refers to any unintended effect on any one or more target, gene, or cellular transcript.

Open reading frame: As used herein, the term “open reading frame” or “ORF” refers to a continuous polynucleotide sequence, for example, a DNA sequence or RNA sequence (e.g., an mRNA sequence), comprising a start codon, a subsequent region comprising a plurality of amino acid-encoding codons, and a terminal stop codon, wherein the region comprising the plurality of amino acid-encoding codons contains no stop codons.

Operably linked: As used herein, the phrase “operably linked” refers to a functional connection between two or more molecules, constructs, transcripts, entities, moieties or the like.

Optionally substituted: Herein a phrase of the form “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g. alkyl) per se is optional.

Part: As used herein, a “part” or “region” of a polynucleotide is defined as any portion of the polynucleotide which is less than the entire length of the polynucleotide.

Peptide: As used herein, “peptide” is less than or equal to 50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long.

Paratope: As used herein, a “paratope” refers to the antigen-binding site of an antibody.

Patient: As used herein, “patient” refers to a subject who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition.

Pharmaceutically acceptable: The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable excipients: The phrase “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

Pharmaceutically acceptable salts: The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17^(th) ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, Pharmaceutical Salts: Properties, Selection, and Use, P. H. Stahl and C. G. Wermuth (eds.), Wiley-VCH, 2008, and Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977), each of which is incorporated herein by reference in its entirety.

Pharmaceutically acceptable solvate: The term “pharmaceutically acceptable solvate,” as used herein, means a compound of the invention wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. For example, solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N′-dimethylformamide (DMF), N,N′-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a “hydrate.”

Pharmacokinetic: As used herein, “pharmacokinetic” refers to any one or more properties of a molecule or compound as it relates to the determination of the fate of substances administered to a living organism. Pharmacokinetics is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as ADME where: (A) Absorption is the process of a substance entering the blood circulation; (D) Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body; (M) Metabolism (or Biotransformation) is the irreversible transformation of parent compounds into daughter metabolites; and (E) Excretion (or Elimination) refers to the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.

Physicochemical: As used herein, “physicochemical” means of or relating to a physical and/or chemical property.

Polypeptide per unit drug (PUD): As used herein, a PUD or product per unit drug, is defined as a subdivided portion of total daily dose, usually 1 mg, pg, kg, etc., of a product (such as a polypeptide) as measured in body fluid or tissue, usually defined in concentration such as pmol/mL, mmol/mL, etc divided by the measure in the body fluid.

Preventing: As used herein, the term “preventing” refers to partially or completely delaying onset of an infection, disease, disorder and/or condition; partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying progression from an infection, a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the infection, the disease, disorder, and/or condition.

Prodrug: The present disclosure also includes prodrugs of the compounds described herein. As used herein, “prodrugs” refer to any substance, molecule or entity which is in a form predicate for that substance, molecule or entity to act as a therapeutic upon chemical or physical alteration. Prodrugs may by covalently bonded or sequestered in some way and which release or are converted into the active drug moiety prior to, upon or after administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

Proliferate: As used herein, the term “proliferate” means to grow, expand or increase or cause to grow, expand or increase rapidly. “Proliferative” means having the ability to proliferate. “Anti-proliferative” means having properties counter to or inapposite to proliferative properties.

Prophylactic: As used herein, “prophylactic” refers to a therapeutic or course of action used to prevent the spread of disease.

Prophylaxis: As used herein, a “prophylaxis” refers to a measure taken to maintain health and prevent the spread of disease. An “immune phrophylaxis” refers to a measure to produce active or passive immunity to prevent the spread of disease.

Protein cleavage site: As used herein, “protein cleavage site” refers to a site where controlled cleavage of the amino acid chain can be accomplished by chemical, enzymatic or photochemical means.

Protein cleavage signal: As used herein “protein cleavage signal” refers to at least one amino acid that flags or marks a polypeptide for cleavage.

Protein of interest: As used herein, the terms “proteins of interest” or “desired proteins” include those provided herein and fragments, mutants, variants, and alterations thereof.

Proximal: As used herein, the term “proximal” means situated nearer to the center or to a point or region of interest.

Pseudouridine: As used herein, pseudouridine refers to the C-glycoside isomer of the nucleoside uridine. A “pseudouridine analog” is any modification, variant, isoform or derivative of pseudouridine. For example, pseudouridine analogs include but are not limited to 1-carboxymethyl-pseudouridine, 1-propynyl-pseudouridine, 1-taurinomethyl-pseudouridine, 1-taurinomethyl-4-thio-pseudouridine, 1-methylpseudouridine (m¹ψ), 1-methyl-4-thio-pseudouridine (m¹s⁴ψ), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m³ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydropseudouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thiouridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1-methyl-pseudouridine, 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine (acp³ψ), and 2′-O-methyl-pseudouridine (ψm).

Purified: As used herein, “purify,” “purified,” “purification” means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection.

Repeated transfection: As used herein, the term “repeated transfection” refers to transfection of the same cell culture with a polynucleotide a plurality of times. The cell culture can be transfected at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times at least 18 times, at least 19 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times or more.

Sample: As used herein, the term “sample” or “biological sample” refers to a subset of its tissues, cells or component parts (e.g. body fluids, including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid and semen). A sample further may include a homogenate, lysate or extract prepared from a whole organism or a subset of its tissues, cells or component parts, or a fraction or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, organs. A sample further refers to a medium, such as a nutrient broth or gel, which may contain cellular components, such as proteins or nucleic acid molecule.

Signal Sequences: As used herein, the phrase “signal sequences” refers to a sequence which can direct the transport or localization of a protein.

Single unit dose: As used herein, a “single unit dose” is a dose of any therapeutic administed in one dose/at one time/single route/single point of contact, i.e., single administration event.

Similarity: As used herein, the term “similarity” refers to the overall relatedness between polymeric molecules, e.g. between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of percent similarity of polymeric molecules to one another can be performed in the same manner as a calculation of percent identity, except that calculation of percent similarity takes into account conservative substitutions as is understood in the art.

Split dose: As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses.

Stable: As used herein “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.

Stabilized: As used herein, the term “stabilize”, “stabilized,” “stabilized region” means to make or become stable.

Stereoisomer: As used herein, the term “stereoisomer” refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

Subject: As used herein, the term “subject” or “patient” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants.

Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

Substantially equal: As used herein as it relates to time differences between doses, the term means plus/minus 2%.

Substantially simultaneously: As used herein and as it relates to plurality of doses, the term means within 2 seconds.

Suffering from: An individual who is “suffering from” a disease, disorder, and/or condition has been diagnosed with or displays one or more symptoms of a disease, disorder, and/or condition.

Susceptible to: An individual who is “susceptible to” a disease, disorder, and/or condition has not been diagnosed with and/or may not exhibit symptoms of the disease, disorder, and/or condition but harbors a propensity to develop a disease or its symptoms. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition (for example, cancer) may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, and/or condition; (5) a family history of the disease, disorder, and/or condition; and (6) exposure to and/or infection with a microbe associated with development of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.

Sustained release: As used herein, the term “sustained release” refers to a pharmaceutical composition or compound release profile that conforms to a release rate over a specific period of time.

Synthetic: The term “synthetic” means produced, prepared, and/or manufactured by the hand of man. Synthesis of polynucleotides or polypeptides or other molecules of the present invention may be chemical or enzymatic.

Vaccine: As used herein, a vaccine is a compound or composition which comprises at least one polynucleotide encoding at least one antigen.

Targeted Cells: As used herein, “targeted cells” refers to any one or more cells of interest. The cells may be found in vitro, in vivo, in situ or in the tissue or organ of an organism. The organism may be an animal, preferably a mammal, more preferably a human and most preferably a patient.

Therapeutic Agent: The term “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.

Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of an agent to be delivered (e.g., nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.

Therapeutically effective outcome: As used herein, the term “therapeutically effective outcome” means an outcome that is sufficient in a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.

Total daily dose: As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose.

Transcription factor: As used herein, the term “transcription factor” refers to a DNA-binding protein that regulates transcription of DNA into RNA, for example, by activation or repression of transcription. Some transcription factors effect regulation of transcription alone, while others act in concert with other proteins. Some transcription factor can both activate and repress transcription under certain conditions. In general, transcription factors bind a specific target sequence or sequences highly similar to a specific consensus sequence in a regulatory region of a target gene. Transcription factors may regulate transcription of a target gene alone or in a complex with other molecules.

Transfection: As used herein, the term “transfection” refers to methods to introduce exogenous nucleic acids into a cell. Methods of transfection include, but are not limited to, chemical methods, plysical treatments and cationic lipids or mixtures.

Translation: As used herein “translation” is the process by which a polynucleotide molecule is processed by a ribosome or ribosomal-like machinery, e.g., cellular or artificial, to produce a peptide or polypeptide.

Transcription: As used herein “transcription” is the process by which a polynucleotide molecule is processed by a polymerase or other enzyme to produce a polynucleotide, e.g., an RNA polynucleotide.

Treating: As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, infection, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, infection, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, infection, disorder, and/or condition.

Unmodified: As used herein, “unmodified” refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the “unmodified” starting molecule for a subsequent modification.

Vaccine: As used herein, the phrase “vaccine” refers to a biological preparation that improves immunity in the context of a particular disease, disorder or condition.

Viral protein: As used herein, the pharse “viral protein” means any protein originating from a virus.

Equivalents and Scope

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the term “consisting of” is thus also encompassed and disclosed.

Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control.

Section and table headings are not intended to be limiting.

EXAMPLES Example 1 Manufacture of Polynucleotides

According to the present invention, the manufacture of polynucleotides and or parts or regions thereof may be accomplished utilizing the methods taught in U.S. Ser. No. 61/800,049 filed Mar. 15, 2013 entitled “Manufacturing Methods for Production of RNA Transcripts”, the contents of which is incorporated herein by reference in its entirety.

Purification methods may include those taught in U.S. Provisional Patent Application No. 61/799,872, U.S. Provisional Patent Application No. 61/794,842, U.S. Provisional Patent Application 61/800,326, each of which is incorporated herein by reference in its entirety.

Detection and characterization methods of the polynucleotides may be performed as taught in U.S. Provisional Patent Application No. 61/799,780 and U.S. Provisional Patent Application No. 61/798,945, each of which is incorporated herein by reference in its entirety.

Characterization of the polynucleotides of the invention may be accomplished using a procedure selected from the group consisting of polynucleotide mapping, reverse transcriptase sequencing, charge distribution analysis, and detection of RNA impurities, wherein characterizing comprises determining the RNA transcript sequence, determining the purity of the RNA transcript, or determining the charge heterogeneity of the RNA transcript. Such methods are taught in, for example, U.S. Provisional Patent Application No. 61/799,905 and U.S. Provisional Patent Application No. 61/800,110, the contents of each of which is incorporated herein by reference in its entirety.

Example 2 Chimeric Polynucleotide Synthesis

Introduction

According to the present invention, two regions or parts of a chimeric polynucleotide may be joined or ligated using triphosphate chemistry.

According to this method, a first region or part of 100 nucleotides or less is chemically synthesized with a 5′ monophosphate and terminal 3′desOH or blocked OH. If the region is longer than 80 nucleotides, it may be synthesized as two strands for ligation.

If the first region or part is synthesized as a non-positionally modified region or part using in vitro transcription (IVT), conversion the 5′monophosphate with subsequent capping of the 3′ terminus may follow.

Monophosphate protecting groups may be selected from any of those known in the art.

The second region or part of the chimeric polynucleotide may be synthesized using either chemical synthesis or IVT methods. IVT methods may include an RNA polymerase that can utilize a primer with a modified cap. Alternatively, a cap of up to 130 nucleotides may be chemically synthesized and coupled to the IVT region or part.

It is noted that for ligation methods, ligation with DNA T4 ligase, followed by treatment with DNAse should readily avoid concatenation.

The entire chimeric polynucleotide need not be manufactured with a phosphate-sugar backbone. If one of the regions or parts encodes a polypeptide, then it is preferable that such region or part comprise a phosphate-sugar backbone.

Ligation is then performed using any known click chemistry, orthoclick chemistry, solulink, or other bioconjugate chemistries known to those in the art.

Synthetic Route

The chimeric polynucleotide is made using a series of starting segments. Such segments include:

(a) Capped and protected 5′ segment comprising a normal 3′OH (SEG. 1)

(b) 5′ triphosphate segment which may include the coding region of a polypeptide and comprising a normal 3′OH (SEG. 2)

(c) 5′ monophosphate segment for the 3′ end of the chimeric polynucleotide (e.g., the tail) comprising cordycepin or no 3′OH (SEG. 3)

After synthesis (chemical or IVT), segment 3 (SEG. 3) is treated with cordycepin and then with pyrophosphatase to create the 5′monophosphate.

Segment 2 (SEG. 2) is then ligated to SEG. 3 using RNA ligase. The ligated polynucleotide is then purified and treated with pyrophosphatase to cleave the diphosphate. The treated SEG.2-SEG. 3 construct is then purified and SEG. 1 is ligated to the 5′ terminus. A further purification step of the chimeric polynucleotide may be performed.

Where the chimeric polynucleotide encodes a polypeptide, the ligated or joined segments may be represented as: 5′UTR (SEG. 1), open reading frame or ORF (SEG. 2) and 3′UTR+PolyA (SEG. 3).

The yields of each step may be as much as 90-95%.

Example 3 PCR for cDNA Production

PCR procedures for the preparation of cDNA are performed using 2× KAPA HIFI™ HotStart ReadyMix by Kapa Biosystems (Woburn, Mass.). This system includes 2× KAPA ReadyMix12.5 μl; Forward Primer (10 uM) 0.75 μl; Reverse Primer (10 uM) 0.75 μl; Template cDNA −100 ng; and dH₂O diluted to 25.0 μl. The reaction conditions are at 95° C. for 5 min. and 25 cycles of 98° C. for 20 sec, then 58° C. for 15 sec, then 72° C. for 45 sec, then 72° C. for 5 min. then 4° C. to termination.

The reverse primer of the instant invention incorporates a poly-T₁₂₀ for a poly-A₁₂₀ in the mRNA. Other reverse primers with longer or shorter poly(T) tracts can be used to adjust the length of the poly(A) tail in the polynucleotide mRNA.

The reaction is cleaned up using Invitrogen's PURELINK™ PCR Micro Kit (Carlsbad, Calif.) per manufacturer's instructions (up to 5 μg). Larger reactions will require a cleanup using a product with a larger capacity. Following the cleanup, the cDNA is quantified using the NANODROP™ and analyzed by agarose gel electrophoresis to confirm the cDNA is the expected size. The cDNA is then submitted for sequencing analysis before proceeding to the in vitro transcription reaction.

Example 4 In Vitro Transcription (IVT)

The in vitro transcription reaction generates polynucletodies containing uniformly modified polynucleotides. Such uniformly modified polynucleotides may comprise a region or part of the polynucleotides of the invention. The input nucleotide triphosphate (NTP) mix is made in-house using natural and un-natural NTPs.

A typical in vitro transcription reaction includes the following:

1 Template cDNA 1.0 μg 2 10x transcription buffer (400 mM 2.0 μl Tris-HCl pH 8.0, 190 mM MgCl₂, 50 mM DTT, 10 mM Spermidine) 3 Custom NTPs (25 mM each) 7.2 μl 4 RNase Inhibitor 20 U 5 T7 RNA polymerase 3000 U 6 dH₂0 Up to 20.0 μl. and 7 Incubation at 37° C. for 3 hr-5 hrs.

The crude IVT mix may be stored at 4° C. overnight for cleanup the next day. 1 U of RNase-free DNase is then used to digest the original template. After 15 minutes of incubation at 37° C., the mRNA is purified using Ambion's MEGACLEAR™ Kit (Austin, Tex.) following the manufacturer's instructions. This kit can purify up to 500 μg of RNA. Following the cleanup, the RNA is quantified using the NanoDrop and analyzed by agarose gel electrophoresis to confirm the RNA is the proper size and that no degradation of the RNA has occurred.

Example 5 Enzymatic Capping

Capping of a polynucleotide is performed as follows where the mixture includes: IVT RNA 60 μg-180 μg and dH₂O up to 72 μl. The mixture is incubated at 65° C. for 5 minutes to denature RNA, and then is transferred immediately to ice.

The protocol then involves the mixing of 10× Capping Buffer (0.5 M Tris-HCl (pH 8.0), 60 mM KCl, 12.5 mM MgCl₂) (10.0 μl); 20 mM GTP (5.0 μl); 20 mM S-Adenosyl Methionine (2.5 μl); RNase Inhibitor (100 U); 2′-O-Methyltransferase (400U); Vaccinia capping enzyme (Guanylyl transferase) (40 U); dH₂O (Up to 28 μl); and incubation at 37° C. for 30 minutes for 60 μg RNA or up to 2 hours for 180 μg of RNA.

The polynucleotide is then purified using Ambion's MEGACLEAR™ Kit (Austin, Tex.) following the manufacturer's instructions. Following the cleanup, the RNA is quantified using the NANODROP™ (ThermoFisher, Waltham, Mass.) and analyzed by agarose gel electrophoresis to confirm the RNA is the proper size and that no degradation of the RNA has occurred. The RNA product may also be sequenced by running a reverse-transcription-PCR to generate the cDNA for sequencing.

Example 6 PolyA Tailing Reaction

Without a poly-T in the cDNA, a poly-A tailing reaction must be performed before cleaning the final product. This is done by mixing Capped IVT RNA (100 μl); RNase Inhibitor (20 U); 10× Tailing Buffer (0.5 M Tris-HCl (pH 8.0), 2.5 M NaCl, 100 mM MgCl₂)(12.0 μl); 20 mM ATP (6.0 μl); Poly-A Polymerase (20 U); dH₂O up to 123.5 μl and incubation at 37° C. for 30 min. If the poly-A tail is already in the transcript, then the tailing reaction may be skipped and proceed directly to cleanup with Ambion's MEGACLEAR™ kit (Austin, Tex.) (up to 500 μg). Poly-A Polymerase is preferably a recombinant enzyme expressed in yeast.

It should be understood that the processivity or integrity of the polyA tailing reaction may not always result in an exact size polyA tail. Hence polyA tails of approximately between 40-200 nucleotides, e.g, about 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 150-165, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164 or 165 are within the scope of the invention.

Example 7 Natural 5′ Caps and 5′ Cap Analogues

5′-capping of polynucleotides may be completed concomitantly during the in vitro-transcription reaction using the following chemical RNA cap analogs to generate the 5′-guanosine cap structure according to manufacturer protocols: 3′-O-Me-m7G(5′)ppp(5′) G [the ARCA cap]; G(5′)ppp(5′)A; G(5′)ppp(5′)G; m7G(5′)ppp(5′)A; m7G(5′)ppp(5′)G (New England BioLabs, Ipswich, Mass.). 5′-capping of modified RNA may be completed post-transcriptionally using a Vaccinia Virus Capping Enzyme to generate the “Cap 0” structure: m7G(5′)ppp(5′)G (New England BioLabs, Ipswich, Mass.). Cap 1 structure may be generated using both Vaccinia Virus Capping Enzyme and a 2′-O methyl-transferase to generate: m7G(5′)ppp(5′)G-2′-O-methyl. Cap 2 structure may be generated from the Cap 1 structure followed by the 2′-O-methylation of the 5′-antepenultimate nucleotide using a 2′-O methyl-transferase. Cap 3 structure may be generated from the Cap 2 structure followed by the 2′-O-methylation of the 5′-preantepenultimate nucleotide using a 2′-O methyl-transferase. Enzymes are preferably derived from a recombinant source.

When transfected into mammalian cells, the modified mRNAs have a stability of between 12-18 hours or more than 18 hours, e.g., 24, 36, 48, 60, 72 or greater than 72 hours.

Example 8 Capping Assays

A. Protein Expression Assay

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be transfected into cells at equal concentrations. 6, 12, 24 and 36 hours post-transfection the amount of protein secreted into the culture medium can be assayed by ELISA. Synthetic polynucleotides that secrete higher levels of protein into the medium would correspond to a synthetic polynucleotide with a higher translationally-competent Cap structure.

B. Purity Analysis Synthesis

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be compared for purity using denaturing Agarose-Urea gel electrophoresis or HPLC analysis. Polynucleotides with a single, consolidated band by electrophoresis correspond to the higher purity product compared to polynucleotides with multiple bands or streaking bands. Synthetic polynucleotides with a single HPLC peak would also correspond to a higher purity product. The capping reaction with a higher efficiency would provide a more pure polynucleotide population.

C. Cytokine Analysis

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be transfected into cells at multiple concentrations. 6, 12, 24 and 36 hours post-transfection the amount of pro-inflammatory cytokines such as TNF-alpha and IFN-beta secreted into the culture medium can be assayed by ELISA. Polynucleotides resulting in the secretion of higher levels of pro-inflammatory cytokines into the medium would correspond to a polynucleotides containing an immune-activating cap structure.

D. Capping Reaction Efficiency

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be analyzed for capping reaction efficiency by LC-MS after nuclease treatment. Nuclease treatment of capped polynucleotides would yield a mixture of free nucleotides and the capped 5′-5-triphosphate cap structure detectable by LC-MS. The amount of capped product on the LC-MS spectra can be expressed as a percent of total polynucleotide from the reaction and would correspond to capping reaction efficiency. The cap structure with higher capping reaction efficiency would have a higher amount of capped product by LC-MS.

Example 9 Agarose Gel Electrophoresis of Modified RNA or RT PCR Products

Individual polynucleotides (200-400 ng in a 20 μl volume) or reverse transcribed PCR products (200-400 ng) are loaded into a well on a non-denaturing 1.2% Agarose E-Gel (Invitrogen, Carlsbad, Calif.) and run for 12-15 minutes according to the manufacturer protocol.

Example 10 Nanodrop Modified RNA Quantification and UV Spectral Data

Modified polynucleotides in TE buffer (1 μl) are used for Nanodrop UV absorbance readings to quantitate the yield of each polynucleotide from an chemical synthesis or in vitro transcription reaction.

Example 11 Formulation of Modified mRNA Using Lipidoids

Polynucleotides are formulated for in vitro experiments by mixing the polynucleotides with the lipidoid at a set ratio prior to addition to cells. In vivo formulation may require the addition of extra ingredients to facilitate circulation throughout the body. To test the ability of these lipidoids to form particles suitable for in vivo work, a standard formulation process used for siRNA-lipidoid formulations may used as a starting point. After formation of the particle, polynucleotide is added and allowed to integrate with the complex. The encapsulation efficiency is determined using a standard dye exclusion assays.

Example 12 Method of Screening for Protein Expression

A. Electrospray Ionization

A biological sample which may contain proteins encoded by a polynucleotide administered to the subject is prepared and analyzed according to the manufacturer protocol for electrospray ionization (ESI) using 1, 2, 3 or 4 mass analyzers. A biologic sample may also be analyzed using a tandem ESI mass spectrometry system.

Patterns of protein fragments, or whole proteins, are compared to known controls for a given protein and identity is determined by comparison.

B. Matrix-Assisted Laser Desorption/Ionization

A biological sample which may contain proteins encoded by one or more polynucleotides administered to the subject is prepared and analyzed according to the manufacturer protocol for matrix-assisted laser desorption/ionization (MALDI).

Patterns of protein fragments, or whole proteins, are compared to known controls for a given protein and identity is determined by comparison.

C. Liquid Chromatography-Mass Spectrometry-Mass Spectrometry

A biological sample, which may contain proteins encoded by one or more polynucleotides, may be treated with a trypsin enzyme to digest the proteins contained within. The resulting peptides are analyzed by liquid chromatography-mass spectrometry-mass spectrometry (LC/MS/MS). The peptides are fragmented in the mass spectrometer to yield diagnostic patterns that can be matched to protein sequence databases via computer algorithms. The digested sample may be diluted to achieve 1 ng or less starting material for a given protein. Biological samples containing a simple buffer background (e.g. water or volatile salts) are amenable to direct in-solution digest; more complex backgrounds (e.g. detergent, non-volatile salts, glycerol) require an additional clean-up step to facilitate the sample analysis.

Patterns of protein fragments, or whole proteins, are compared to known controls for a given protein and identity is determined by comparison.

Example 13 Cyclization and/or Concatemerization

According to the present invention, a polynucleotide may be cyclized, or concatemerized, to generate a translation competent molecule to assist interactions between poly-A binding proteins and 5′-end binding proteins. The mechanism of cyclization or concatemerization may occur through at least 3 different routes: 1) chemical, 2) enzymatic, and 3) ribozyme catalyzed. The newly formed 5′-/3′-linkage may be intramolecular or intermolecular.

In the first route, the 5′-end and the 3′-end of the nucleic acid contain chemically reactive groups that, when close together, form a new covalent linkage between the 5′-end and the 3′-end of the molecule. The 5′-end may contain an NHS-ester reactive group and the 3′-end may contain a 3′-amino-terminated nucleotide such that in an organic solvent the 3′-amino-terminated nucleotide on the 3′-end of a synthetic mRNA molecule will undergo a nucleophilic attack on the 5′-NHS-ester moiety forming a new 5′-/3′-amide bond.

In the second route, T4 RNA ligase may be used to enzymatically link a 5′-phosphorylated nucleic acid molecule to the 3′-hydroxyl group of a nucleic acid forming a new phosphorodiester linkage. In an example reaction, 1 μg of a nucleic acid molecule is incubated at 37° C. for 1 hour with 1-10 units of T4 RNA ligase (New England Biolabs, Ipswich, Mass.) according to the manufacturer's protocol. The ligation reaction may occur in the presence of a split polynucleotide capable of base-pairing with both the 5′- and 3′-region in juxtaposition to assist the enzymatic ligation reaction.

In the third route, either the 5′- or 3′-end of the cDNA template encodes a ligase ribozyme sequence such that during in vitro transcription, the resultant nucleic acid molecule can contain an active ribozyme sequence capable of ligating the 5′-end of a nucleic acid molecule to the 3′-end of a nucleic acid molecule. The ligase ribozyme may be derived from the Group I Intron, Group I Intron, Hepatitis Delta Virus, Hairpin ribozyme or may be selected by SELEX (systematic evolution of ligands by exponential enrichment). The ribozyme ligase reaction may take 1 to 24 hours at temperatures between 0 and 37° C.

Example 14 Antigen Polynucleotides

Polynucleotides used in the studies hereing which encode certain infectious agent antigens or variants thereof are shown in Table 28.

TABLE 28 Antigen polynucleotides (RNA vaccine) Construct Number Gene ID Description Construct 1 120552 Flu PR8 HA HAPR8_Ferritin_Hs3 ferritin 2 120553 flu 1999NC HA HA1999NC_Ferritin_Hs3 ferritin 3 125387 H5N1 HA antigen H5N1_HA_NIBRG-14 4 125388 H1N1 PR8 HA CurevacPR8HA_MT5U_Hs3U antigen with MT 5U/3U 5 135929 Influenza HA HA_A/Mallard/Netherlands/12/2000_H7N3_Hs3U antigen 6 135930 Influenza HA HA_A/Puerto Rico/8/1934_H1N1_Hs3U antigen 7 135931 Influenza HA HA_A/Viet Nam/850/2009_H1N1_Hs3U antigen 8 135932 Influenza HA HA_A/New Calcedonia/20/99_H1N1_Hs3U antigen 9 135933 Influenza HA HA_A/Vietnam/1203/2004_H5N1_Hs3U antigen 10 135934 Influenza HA HA_A/Hong Kong/1073/99_H9N2_Hs3U antigen 11 135935 Influenza HA HA_A/Wisconsin/67/2005_H3N2_Hs3U antigen 12 135936 Influenza HA HA_A/Hong Kong/1/1968_H3N2_Hs3U antigen 13 136473 flu HA antigen A/duck/Anhui/SC702/2013(H7N9)_Hs3U 14 136754 C diff antigen Cdiff_toxinA.truc_nMyc.cFLAG_Hs3U 15 136755 C diff antigen Cdiff_toxinB.truc_nMyc.cFLAG_Hs3U 16 136756 C diff antigen Cdiff_cdtA.truc_nMyc.cFLAG_Hs3U 17 136757 C diff antigen Cdiff_cdtB.truc_nMyc.cFLAG_Hs3U 18 120554 Dengue strain 2 DEN2_DIII_Ferritin_Hs3 domain 3 ferritin 19 120555 Dengue strain 3 DEN3_DIII_Ferritin_Hs3 domain 3 ferritin 20 120556 Dengue strain 4 DEN4_DIII_Ferritin_Hs3 domain 3 ferritin 21 120557 dengue strain 1-4 Dengue_TDIII_Hs3 Domain 3 22 121542 Dengue strain 1 DEN1_DIII_Ferritin_Corr_Hs3 domain 3 ferritin 23 131502 Dengue 2, DEN2_D2Y98P_PrME_Hs3 D2Y98P strain, PrME transmembrane antigen 24 131503 Dengue 2, DEN2_D2Y98P_PrME80_Hs3 D2Y98P strain, PrME secreted antigen 25 131507 Dengue 2, DEN2_D2Y98P_PrME80_ScFv.aDEC205.FLAG_Hs3 D2Y98P strain, PrME secreted antigen with dendritic targeting ScFv against mouse DEC205 26 136358 Staph aureus SpA_sec.D.wt.nXpress.cHA_VKsp_Hs3U antigen 27 136359 Staph aureus SpA_intra.D.kkaa.nFLAG.cMyc_Hs3U antigen 28 136360 Staph aureus SpA_mem.D.kkaa.nFLAG.cMyc_CD28mem_Hs3U antigen 29 136361 Staph aureus SpA_sec.D.kkaa.nFLAG.cMyc_VKsp_Hs3U antigen 30 136362 Staph aureus SpA_intra.D.wt.nXpress.cHA_Hs3U antigen 31 136363 Staph aureus SpA_mem.D.wt.nXpress.cHA_CD28mem_Hs3U antigen 32 136364 Staph aureus SpA_sec.D.wt_VKsp antigen 33 136758 MRSA IsdA MRSA_IsdA.truc_nMyc.cFLAG_Hs3U antigen 34 136759 MRSA IsdB MRSA_IsdB.truc_nMyc.cFLAG_Hs3U antigen 35 136763 MRSA SDRD MRSA_sdrd.trac_nMyc.cFLAG_Hs3U antigen 36 136764 MRSA SDRE MRSA_sdre.truc_nMyc.cFLAG_Hs3U antigen 37 136765 MRSA MECA MRSA_mecA.truc_nMyc.cFLAG_Hs3U antigen 38 139325 MRSA SDRD MRSA_sdrd.contig1._FLAG_Hs3U antigen 39 139326 MRSA SDRD MRSA_sdrd.Contig2._FLAG_Hs3U antigen 40 139327 MRSA SDRE MRSA_sdre.Contig1._FLAG_Hs3U antigen 41 139328 MRSA SDRE MRSA_sdre.Contig2._FLAG_Hs3U antigen 42 140470 MRSA ISDA MRSA_IsdA.fl_FLAG_Hs3U antigen 43 139277 MRSA MECA MRSA_mecA.fl._FLAG_Hs3U antigen 44 136747 ETEC antigen ETEC.eltA(S63K/R192G/L211A)_nMyc.cFLAG_Hs3U 45 136748 ETEC antigen ETEC.eltB_nMyc.cFLAG_Hs3U 46 136749 ETEC antigen ETEC.Sta3(A14Q)_nMyc.cFLAG_Hs3U 47 136750 ETEC antigen ETEC.etpA._nMyc.cFLAG_Hs3U 48 136751 ETEC antigen ETEC.etpB._nMyc.cFLAG_Hs3U 49 136752 ETEC antigen ETEC.EatA_nMyc.cFLAG_Hs3U 50 136753 ETEC antigen ETEC_cssA_nMyc.cFLAG_Hs3U 51 136747 ETEC antigen ETEC.eltA(S63K/R192G/L211A)_nMyc.cFLAG_Hs3U 52 142544 ETEC antigen ETEC.etpB.fl_FLAG_Hs3U 53 136749 ETEC antigen ETEC.Sta3(A14Q)_nMyc.cFLAG_Hs3U 54 136753 ETEC CSSA ETEC_cssA_nMyc.cFLAG_Hs3U antigen 55 139323 ETEC EATA ETEC_EatA.contig1._FLAG_Hs3U antigen 56 139324 ETEC EATA ETEC_EatA.contig2._FLAG_Hs3U antigen 57 139321 ETEC EPTA ETEC_eptA.contig1._FLAG_Hs3U antigen 58 139322 ETEC ETPA ETEC_etpA.contig2._FLAG_Hs3U antigen 59 136760 Tuberculosis TB_Ag85A_nMyc.cFLAG_Hs3U antigen 60 136761 Tuberculosis TB_Ag85B_nMyc.cFLAG_Hs3U antigen 61 136762 Tuberculosis TB_TB10.4_nMyc.cFLAG_Hs3U antigen 62 136335 Cholera toxin B CholeraToxB.H78A.FLAG_VKsp_Hs3U 63 144097 vaccine Influenza PR8HA.Stalk.pscaffold_Hs3U HA antigen (nanoscaffold) 64 144094 vaccine Influenza PR8HA.stalk.HbCore.monoRNA_Hs3U HA antigen (splitcore) 65 144095 vaccine Influenza PR8HA.stalk.HbCoreC.RKR_Hs3U HA antigen (splitcore) 66 144096 vaccine Influenza PR8HA.stalk.HbCoreN.RKR_Hs3U HA antigen (splitcore) 67 144098 vaccine Influenza PR8HA.headless.Stalk.ugly(N76D/N270D)_Hs3U HA antigen; aglycosylated 68 144099 vaccine Influenza PR8HA.headless.Stalk.ugly(N27D/ HA antigen; N28D/N40D/N76D/N270D)_Hs3U aglycosylated 69 150088 Vaccine MERS MERS-CoV_ProteinS/EMC/2012.V5_Hs3U CoV spike protein (V5 epitope tagged) 70 139276 vaccine MRSA MRSA_IsdB.fl._FLAG_Hs3U IsdB antigen 71 149385 MERS-CoV DPPIV.Fc_HS3U passive immunity 72 150092 Vaccine HEV71 HEV71.VP1.2.3.VP5_HS3U (polycistronic antigen containing VP1 VP2 & VP3) each separated by a furin cleavage site RKR 73 144093 vaccine Influenza PR8HA.Stalk_Hs3U HA antigen 74 Vaccine Klebsiella Beta-lactamase SHV-2 pneumoniae: cefotaxime, ceftazidime and other broad spectrum cephalosporins. 75 Vaccine PsaA SP Pneumococcal Streptococcus surface adhesin A pneumoniae surface adhesin A Fragment (22-309) 76 Vaccine Pseudomonas type 2 Pseudomonas Cephalosporinase aeruginosa ampC beta-lactamase 77 Vaccine Beta-lactamase class Pseudomonas B VIM-2 aeruginosa VIM-2, a carbapenem- hydrolyzing metallo-beta- lactamase 78 Vaccine Beta-lactamase LCR-1 Pseudomonas aeruginosa, LCR-1 hydrolyzes methicillin. 79 Vaccine Staph Staph aureus TSST1 aureus Toxic shock syndrome toxin-1 80 Vaccine Staph Staph aureus PVL toxin aureus PVL toxin 81 vaccine Pneumolysin toxoid Streptococcus pneumoniae Pneumolysin toxoid 82 Full length with Streptococcus pneumoniae mutations of ppaC W433F, D385N, and C428G

Additional antigens including wild type and engineered antigens are taught in Tables 29 and 30.

Pan-Flu NAVs

In one embodiment the “HA head” region of one or more influenza virus strains is removed leaving only the stem or transmembrane region. This region or multiple regions if selected, is then used as the immunogen to screen for optimal response to a viral challenge. As such broad neutralization could be achieved against multiple strains or a multi-response to one strain. The resultant vaccine would represent a pan-influenza vaccine.

Further, a pan-influenza vaccine could also be combined with any immune potentiator disclosed herein.

Polynucleotides used in the studies herein which encode certain infectious agent antigens or variants thereof may be formulated in any of the formulations described herein including LNPs and may be administered intradermally (ID) or intramuscularly (IM) or by any suitable route.

Disclosed in Table 29 are the HA regions, transmembrane and cytoplasmic regions of several influenza strains to be used in the stem vaccination generation protocol just described.

TABLE 29 Wild type antigens encoded by NAV polynucleotides Full length HA AA Virus Strain Sequence HA1 HA2 TM CY H1N1 A/PR8/34 (SEQ ID NO: 931) (SEQ ID NO: (SEQ ID NO: (SEQ (SEQ MKANLLVLLCALAAA 932) 933) ID ID DADTICIGYHANNSTD MKANLLVLL GLFGAIAG NO: NO: TVDTVLEKNVTVTHS CALAAADAD FIEGGWTG 934) 935) VNLLEDSHNGKLCRL TICIGYHANN MIDGWYG ILAI SFW KGIAPLQLGKCNIAGW STDTVDTVLE YHHQNEQ YST MCSN LLGNPECDPLLPVRSW KNVTVTHSV GSGYAADQ VAS GSLQ SYIVETPNSENGICYPG NLLEDSHNG KSTQNAIN SLVL CRICI DFIDYEELREQLSSVSS KLCRLKGIAP GITNKVNT LVSL PERFEIFPKESSWPNHN LQLGKCNIAG VIEKMNIQF GAI TNGVTAACSHEGKSSF WLLGNPECD TAVGKEFN YRNLLWLTEKEGSYP PLLPVRSWSY KLEKRMEN KLKNSYVNKKGKEVL IVETPNSENGI LNKKVDD VLWGIHHPPNSKEQQ CYPGDFIDYE GFLDIWTY NLYQNENAYVSVVTS ELREQLSSVS NAELLVLL NYNRRFTPEIAERPKV SFERFEIFPKE ENERTLDF RDQAGRMNYYWTLL SSWPNHNTN HDSNVKNL KPGDTIIFEANGNLIAP GVTAACSHE YEKVKSQL MYAFALSRGFGSGIITS GKSSFYRNLL KNNAKEIG NASMHECNTKCQTPL WLTEKEGSY NGCFEFYH GAINSSLPYQNIHPVTI PKLKNSYVN KCDNECME GECPKYVRSAKLRMV KKGKEVLVL SVRNGTYD TGLRNNPSIQSRGLFG WGIHHPPNSK YPKYSEES AIAGFIEGGWTGMIDG EQQNLYQNE KLNREKVD WYGYHHQNEQGSGY NAYVSVVTS GVKLESMG AADQKSTQNAINGITN NYNRRFTPEI IYQ KVNTVIEKMNIQFTAV AERPKVRDQ GKEFNKLEKRMENLN AGRMNYYW KKVDDGFLDIWTYNA TLLKPGDTIIF ELLVLLENERTLDFHD EANGNLIAPM SNVKNLYEKVKSQLK YAFALSRGFG NNAKEIGNGCFEFYHK SGIITSNASM CDNECMESVRNGTYD HECNTKCQTP YPKYSEESKLNREKVD LGAINSSLPY GVKLESMGIYQILAIYS QNIHPVTIGE TVASSLVLLVSLGAISF CPKYVRS AK WMCSNGSLQCRICI LRMVTGLRN NPSIQSR H1N1 A/New (SEQ ID NO: 936) (SEQ ID NO: (SEQ ID NO: (SEQ (SEQ Caledonia/ MKAKLLVLLCTFTAT 937) 938) ID ID 20/1999 YADTICIGYHANNSTD MKAKLLVLL GLFGAIAG NO: NO: TVDTVLEKNVTVTHS CTFTATYADT FIEGGWTG 939) 940) VNLLEDSHNGKLCLL ICIGYHANNS MVDGWYG ILAI SFW KGIAPLQLGNCSVAG TDTVDTVLE YHHQNEQ YST MCSN WILGNPECELLISKES KNVTVTHSV GSGYAADQ VAS GSLQ WSYIVETPNPENGTCY NLLEDSHNG KSTQNAIN SLVL CRICI PGYFADYEELREQLSS KLCLLKGIAP GITNKVNS LVSL VSSFERFEIFPKESSWP LQLGNCSVA VIEKMNTQ GAI NHTVTGVSASCSHNG GWILGNPECE FTAVGKEF KSSFYRNLLWLTGKN LLISKESWSYI NKLERRME GLYPNLSKSYVNNKE VETPNPENGT NLNKKVD KEVLVLWGVHHPPNI CYPGYFADY DGFLDIWT GNQRALYHTENAYVS EELREQLSSV YNAELLVL VVSSHYSRRFTPEIAK SSFERFEIFPK LENERTLD RPKVRDQEGRINYYW ESSWPNHTVT FHDSNVKN TLLEPGDTIIFEANGNL GVSASCSHN LYEKVKSQ IAPWYAFALSRGFGSG GKSSFYRNLL LKNNAKEI IITSNAPMDECDAKCQ WLTGKNGLY GNGCFEFY TPQGAINSSLPFQNVH PNLSKSYVNN HKCNNEC PVTIGECPKYVRSAKL KEKEVLVLW MESVKNGT RMVTGLRNIPSIQSRG GVHHPPNIGN YDYPKYSE LFGAIAGFIEGGWTGM QRALYHTEN ESKLNREKI VDGWYGYHHQNEQG AYVSVVSSH DGVKLESM SGYAADQKSTQNAIN YSRRFTPEIA GVYQ GITNKVNSVIEKMNTQ KRPKVRDQE FTAVGKEFNKLERRM GRINYYWTL ENLNKKVDDGFLDIW LEPGDTIIFEA TYNAELLVLLENERTL NGNLIAPWY DFHDSNVKNLYEKVK AFALSRGFGS SQLKNNAKEIGNGCFE GIITSNAPMD FYHKCNNECMESVKN ECDAKCQTP GTYDYPKYSEESKLNR QGAINSSLPF EKIDGVKLESMGVYQI QNVHPVTIGE LAIYSTVASSLVLLVSL CPKYVRSAK GAISFWMCSNGSLQCR LRMVTGLRNI ICI PSIQSR H10N8 A/JX346/ (SEQ ID NO: 941) (SEQ ID NO: (SEQ ID NO: (SEQ (SEQ 2013 MYKIVVIIALLGAVKG 942) 943) ID ID LDKICLGHHAVANGTI MYKIVVIIAL RGLFGAIA NO: NO: VKTLTNEQEEVTNATE LGAVKGLDKI GFLENGWE 944) 945) TVESTGINRLCMKGRK CLGHHAVAN GMVDGWY WFS CLKN HKDLGNCHPIGMLIGT GTIVKTLTNE GFRHQNAQ FGA GNM PACDLHLTGMWDTLI QEEVTNATET GTGQAAD SCFV RCTIC ERENAIAYCYPGATVN VESTGINRLC YKSTQAAI LLA I VEALRQKIMESGGINK MKGRKHKDL DQITGKLN VVM ISTGFTYGSSINSAGTT GNCHPIGMLI RLVEKTNT GLFF RACMRNGGNSFYAEL GTPACDLHLT EFESIESEFS F KWLVSKSKGQNFPQT GMWDTLIER EIEHQIGNV TNTYRNTDTAEHLIM ENAIAYCYPG INWTKDSIT WGIHHPSSTQEKNDLY ATVNVEALR DIWTYQAE GTQSLSISVGSSTYRN QKIMESGGIN LLVAMENQ NFVPVVGARPQVNGQ KISTGFTYGS HTIDMADS SGRIDFHWTLVQPGDN SINSAGTTRA EMLNLYER ITFSHNGGLIAPSRVSK CMRNGGNSF VRKQLRQN LIGRGLGIQSDAPIDNN YAELKWLVS AEEDGKGC CESKCFWRGGSINTRL KSKGQNFPQT FEIYHACD PFQNLSPRTVGQCPKY TNTYRNTDT DSCMESIR VNRRSLMLATGMRNV AEHLIMWGIH NNTYDHSQ PELIQGRGLFGAIAGFL HPSSTQEKND YREEALLN ENGWEGMVDGWYGF LYGTQSLSIS RLNINPVTL RHQNAQGTGQAADY VGSSTYRNNF SSGYKDIIL KSTQAAIDQITGKLNR VPVVGARPQ LVEKTNTEFESIESEFS VNGQSGRIDF EIEHQIGNVINWTKDSI HWTLVQPGD TDIWTYQAELLVAME NITFSHNGGLI NQHTIDMADSEMLNL APSRVSKLIG YERVRKQLRQNAEED RGLGIQSDAP GKGCFEIYHACDDSC IDNNCESKCF MESIRNNTYDHSQYRE WRGGSINTRL EALLNRLNINPVTLSS PFQNLSPRTV GYKDIILWFSFGASCF GQCPKYVNR VLLAVVMGLFFFCLK RSLMLATGM NGNMRCTICI RNVPELIQG H7N9 A/Anhui/1/ (SEQ ID NO: 946) (SEQ ID NO: (SEQ ID NO: (SEQ (SEQ 2013 MNTQILVFALIAIIPTN 947) 948) ID ID ADKICLGHHAVSNGT MNTQILVFAL RGLFGAIA NO: NO: KVNTLTERGVEVVNA IAIIPTNADKI GFIENGWE 949) 950) TETVERTNIPRICSKGK CLGHHAVSN GLIDGWYG WFS CVKN KTVDLGQCGLLGTITG GTKVNTLTER FRHQNAQG FGA GNM PPQCDQFLEFSADLIIE GVEVVNATE EGTAADYK SCFI RCTIC RREGSDVCYPGKFVN TVERTNIPRIC STQSAIDQI LLAI I EEALRQILRESGGIDKE SKGKKTVDL TGKLNRLIE VMG AMGFTYSGIRTNGATS GQCGLLGTIT KTNQQFELI LVFI ACRRSGSSFYAEMKW GPPQCDQFLE DNEFNEVE LLSNTDNAAFPQMTKS FSADLIIERRE KQIGNVIN YKNTRKSPALIVWGIH GSDVCYPGK WTRDSITE HSVSTAEQTKLYGSGN FVNEEALRQI VWSYNAEL KLVTVGSSNYQQSFVP LRESGGIDKE LVAMENQ SPGARPQVNGQSGRID AMGFTYSGIR HTIDLADSE FHWLMLNPNDTVTFS TNGATSACR MDKLYER FNGAFIAPDRASFLRG RSGSSFYAEM VKRQLREN KSMGIQSGVQVDANC KWLLSNTDN AEEDGTGC EGDCYHSGGTIISNLPF AAFPQMTKS FEIFHKCDD QNIDSRAVGKCPRYV YKNTRKSPAL DCMASIRN KQRSLLLATGMKNVP IVWGIHHSVS NTYDHSKY EIPKGRGLFGAIAGFIE TAEQTKLYGS REEAMQNR NGWEGLIDGWYGFRH GNKLVTVGS IQIDPVKLS QNAQGEGTAADYKST SNYQQSFVPS SGYKDVIL QSAIDQITGKLNRLIEK PGARPQVNG TNQQFELIDNEFNEVE QSGRIDFHWL KQIGNVINWTRDSITE MLNPNDTVT VWSYNAELLVAMENQ FSFNGAFIAP HTIDLADSEMDKLYER DRASFLRGKS VKRQLRENAEEDGTG MGIQSGVQV CFEIFHKCDDDCMASI DANCEGDCY RNNTYDHSKYREEAM HSGGTIISNLP QNRIQIDPVKLSSGYK FQNIDSRAVG DVILWFSFGASCFILLA KCPRYVKQR IVMGLVFICVKNGNM SLLLATGMK RCTICI NVPEIPKG H7N9 .A/Jiangsu/ (SEQ ID NO: 951) (SEQ ID NO: (SEQ ID NO: (SEQ (SEQ 2/2013 MNTQILVFALIAIIPTN 952) 953) ID ID (H242) ADKICLGHHAVSNGT MNTQILVFAL RGLFGAIA NO: NO: KVNTLTERGVEVVNA IAIIPTNADKI GFIENGWE 954) 955) TETVERTNIPRICSKGK CLGHHAVSN GLIDGWYG WFS CVKN MTVDLGQCGLLGTITG GTKVNTLTER FRHQNAQG FGA GNM PPQCDQFLEFSADLIIE GVEVVNATE EGTAADYK SCFI RCTIC RREGSDVCYPGKFVN TVERTNIPRIC STQSAIDQI LLAI I EEALRQILRESGGIDKE SKGKMTVDL TGKLNRLIE VMG AMGFTYSGIRTNGATS GQCGLLGTIT KTNQQFELI LVFI ACRRSGSSFYAEMKW GPPQCDQFLE DNEFNEVE LLSNTDNAAFPQMTKS FSADLIIERRE KQIGNVIN YKNTRKSPALIVWGIH GSDVCYPGK WTRDSITE HSVSTAEQTKLYGSGN FVNEEALRQI VWSYNAEL KLVTVGSSNYQQSFVP LRESGGIDKE LVAMENQ SPGARPQVNGLSGRID AMGFTYSGIR HTIDLADSE FHWLMLNPNDTVTFS TNGATSACR MDKLYER FNGAFIAPDRASFLRG RSGSSFYAEM VKRQLREN KSMGIQSGVQVDANC KWLLSNTDN AEEDGTGC EGDCYHSGGTIISNLPF AAFPQMTKS FEIFHKCDD QNIDSRAVGKCPRYV YKNTRKSPAL DCMASIRN KQRSLLLATGMKNVP IVWGIHHSVS NTYDHSKY EIPKGRGLFGAIAGFIE TAEQTKLYGS ReEAMQNR NGWEGLIDGWYGFRH GNKLVTVGS IQIDPVKLS QNAQGEGTAADYKST SNYQQSFVPS SGYKDVIL QSAIDQITGKLNRLIEK PGARPQVNG TNQQFELIDNEFNEVE LSGRIDFHWL KQIGNVINWTRDSITE MLNPNDTVT VWSYNAELLVAMENQ FSFNGAFIAP HTIDLADSEMDKLYER DRASFLRGKS VKRQLRENAEEDGTG MGIQSGVQV CFEIFHKCDDDCMASI DANCEGDCY RNNTYDHSKYReEAM HSGGTIISNLP QNRIQIDPVKLSSGYK FQNIDSRAVG DVILWFSFGASCFILLA KCPRYVKQR IVMGLVFICVKNGNM SLLLATGMK RCTICI NVPEIPKG In the Table, TM stands for transmembrane and CY stands for cytoplasmic.

Following the vaccine generation strategy above, engineered antigens may also be used to develop pan-flu vaccines. Such constructs are shown in Table 30.

TABLE 30 Engineered antigens encoded by NAV polynucleotides Config- Protein SEQ ID Virus Strain uration engineering Full length Sequence NO. H1N1 PR8/34 HA(PR8)- fusion protein MKANLLVLLCALAAADADTICIGY 956 Ferritin of HA HANNSTDTVDTVLEKNVTVTHSV antigen with NLLEDSHNGKLCRLKGIAPLQLGK ferritin (H CNIAGWLLGNPECDPLLPVRSWSY pylori) to IVETPNSENGICYPGDFIDYEELRE form QLSSVSSFERFEIFPKESSWPNHNT nanoscaffold, NGVTAACSHEGKSSFYRNLLWLTE secreted KEGSYPKLKNSYVNKKGKEVLVL WGIHHPPNSKEQQNLYQNENAYV SVVTSNYNRRFTPEIAERPKVRDQ AGRMNYYWTLLKPGDTIIFEANGN LIAPMYAFALSRGFGSGIITSNASM HECNTKCQTPLGAINSSLPYQNIHP VTIGECPKYVRSAKLRMVTGLRNN PSIQSRGLFGAIAGFIEGGWTGMID GWYGYHHQNEQGSGYAADQKST QNAINGITNKVNTVIEKMNIQFTA VGKEFNKLEKRMENLNKKVDDGF LDIWTYNAELLVLLENERTLDFHD SNVKNLYEKVKSQLKNNAKEIGN GCFEFYHKCDNECMESVRNGTYD YPKYSEESKLNREKVDSGGDIIKLL NEQVNKEMQSSNLYMSMSSWCYT HSLDGAGLFLFDHAAEEYEHAKK LIIFLNENNVPVQLTSISAPEHKFEG LTQIFQKAYEHEQHISESINNIVDH AIKSKDHATFNFLQWYVAEQHEEE VLFKDILDKIELIGNENHGLYLADQ YVKGIAKSRKS H1N1 A/New HA fusion protein MKAKLLVLLCTFTATYADTICIGY 957 Caledonia/ (NC1999)- of HA HANNSTDTVDTVLEKNVTVTHSV 20/1999 Ferritin antigen with NLLEDSHNGKLCLLKGIAPLQLGN (1999 ferritin (H CSVAGWILGNPECELLISKESWSYI NC) pylori) to VETPNPENGTCYPGYFADYEELRE form QLSSVSSFERFEIFPKESSWPNHTV nanoscaffold, TGVSASCSHNGKSSFYRNLLWLTG secreted KNGLYPNLSKSYVNNKEKEVLVL WGVHHPPNIGNQRALYHTENAYV SVVSSHYSRRFTPEIAKRPKVRDQE GRINYYWTLLEPGDTIIFEANGNLI APWYAFALSRGFGSGIITSNAPMD ECDAKCQTPQGAINSSLPFQNVHP VTIGECPKYVRSAKLRMVTGLRNI PQRETRGLFGAIAGFIEGGWTGMV DGWYGYHHQNEQGSGYAADQKS TQNAINGITNKVNSVIEKMNTQFT AVGKEFNKLERRMENLNKKVDDG FLDIWTYNAELLVLLENERTLDFH DSNVKNLYEKVKSQLKNNAKEIG NGCFEFYHKCNNECMESVKNGTY DYPKYSEESKLNREKIDSGGDIIKL LNEQVNKEMQSSNLYMSMSSWCY THSLDGAGLFLFDHAAEEYEHAK KLIIFLNENNVPVQLTSISAPEHKFE GLTQIFQKAYEHEQHISESINNIVD HAIKSKDHATFNFLQWYVAEQHE EEVLFKDILDKIELIGNENHGLYLA DQYVKGIAKSRKSGS H1N1 PR8/34 HA1(-) Headless HA MKANLLVLLCALAAADADTICIGY 958 stem only antigen (Stem HANNSTDTVDTVLEKNVTVTHSV HA only), NLLEDSHNGKLCGGGGCNTKCQT antigen transmembrane, PLGAINSSLPYQNIHPVTIGECPKY VRSAKLRMVTGLRNIPSIQSRGLFG AIAGFIEGGWTGMIDGWYGYHHQ NEQGSGYAADQKSTQNAINGITNK VNTVIEKMNIQFTAVGKEFNKLEK RMENLNKKVDDGFLDIWTYNAEL LVLLENERTLDFHDSNVKNLYEKV KSQLKNNAKEIGNGCFEFYHKCDN ECMESVRNGTYDYPKYSEESKLNR EKVDGVKLESMGIYQILAIYSTVAS SLVLLVSLGAISFWMCSNGSLQCRI CI H1N1 PR8/34 Mono Headless HA MKANLLVLLCALAAADADTICIGY 959 glyco- antigen (Stem HANNSTDTVDTVLEKNVTVTHSV sylated only), NLLEDSHNGKLCGGGGCNTKCQT HA 1(-) transmembrane, PLGAIDSSLPYQNIHPVTIGECPKY stem only mongly- VRSAKLRMVTGLRNIPSIQSRGLFG HA cosylated  AIAGFIEGGWTGMIDGWYGYHHQ antigen by N76D, NEQGSGYAADQKSTQNAINGITNK N270D VNTVIEKMNIQFTAVGKEFNKLEK RMENLNKKVDDGFLDIWTYNAEL LVLLENERTLDFHDSNVKNLYEKV KSQLKNNAKEIGNGCFEFYHKCDN ECMESVRDGTYDYPKYSEESKLNR EKVDGVKLESMGIYQILAIYSTVAS SLVLLVSLGAISFWMCSNGSLQCRI CI H1N1 PR8/34 aglycosyla Headless HA MKANLLVLLCALAAADADTICIGY 960 ted HA 1 antigen (Stem HADDSTDTVDTVLEKDVTVTHSV (-) Stem only), NLLEDSHNGKLCGGGGCNTKCQT only HA transmembrane, PLGAIDSSLPYQNIHPVTIGECPKY antigen aglycosylated VRSAKLRMVTGLRNIPSIQSRGLFG by AIAGFIEGGWTGMIDGWYGYHHQ N27D,N28D, NEQGSGYAADQKSTQNAINGITNK N40D, N76D, VNTVIEKMNIQFTAVGKEFNKLEK N279D RMENLNKKVDDGFLDIWTYNAEL LVLLENERTLDFHDSNVKNLYEKV KSQLKNNAKEIGNGCFEFYHKCDN ECMESVRDGTYDYPKYSEESKLNR EKVDGVKLESMGIYQILAIYSTVAS SLVLLVSLGAISFWMCSNGSLQCRI CI H1N1 PR8/34 HA1(-) Headless HA MKANLLVLLCALAAADADTICIGY 961 stem HA- antigen (stem HANNSTDTVDTVLEKNVTVTHSV ferritin only) fused to NLLEDSHNGKLCGGGGCNTKCQT ferritin PLGAINSSLPYQNIHPVTIGECPKY nanoscaffold, VRSAKLRMVTGLRNIPSIQSRGLFG secreted AIAGFIEGGWTGMIDGWYGYHHQ NEQGSGYAADQKSTQNAINGITNK VNTVIEKMNIQFTAVGKEFNKLEK RMENLNKKVDDGFLDIWTYNAEL LVLLENERTLDFHDSNVKNLYEKV KSQLKNNAKEIGNGCFEFYHKCDN ECMESVRNGTYDYPKYSEESKLNR EKVDSGGDIIKLLNEQVNKEMQSS NLY MSMSSWCYTHSLDGAGLFLFDHA AEEYEHAKKLIIFLNENNVPVQLTS ISAPEHKFEGLT QIFQKAYEHEQHISESINNIVDHAIK SKDHATFNFLQWYVAEQHEEEVL FKDILDKIELI GNENHGLYLADQYVKGIAKSRKS GS

Example 15 Influenza Study—H1N1Hemagglutinin (HA) Antigen

The instant study was designed in two phases, first to test the the immunogenicity of mRNA vaccines encoding HA from Influenza A/PR/8 (H1N1) in mice and second to test the efficacy of candidate influenza vaccines in mice against a lethal challenge with influenza (INFV) A/PR/8/34 (H1N1). The study design is outlined in Table 31. The NAV polynucleotide used in the study was construct 4 from Table 28.

In phase I of this study, mice were vaccinated on week 0 and 3 via intravenous (IV), intramuscular (IM), or intradermal (ID) routes. One group remained unvaccinated and one was administered inactivated PR8 antigen. Serum was collected from each mouse on weeks 1, 3 (pre-dose), and 5. Individual bleeds were tested for anti-HA activity via virus neutralization assay and HA inhibition (HAI) from all three time points and pooled samples from week 5 only were tested by Western blot using A/PR/8/34 (H1N1).

Phase II

Since the desired immune response was achieved (HAI titer >40), phase II of the study was performed. In phase II, mice were challenged with a lethal dose (10×LD₉₀; ˜100 plaque-forming units; PFU) of A/PR/8/34 (H1N1) via intranasal (IN) instillation. Mice were monitored for weights, health, and survival for 14 days.

This study tested the immunogenicity of mRNA vaccines encoding HA from Influenza A/PR/8 (H1N1) in mice. The study utilized 12 groups of five BALB/c female mice. Mice were vaccinated on week 0 and 3 via intranasal (positive control), intravenous, intramuscular, or intradermal routes. One group was unvaccinated and one administered inactivated PR8 antigen via intranasal vaccination.

This study tested whether candidate ribonucleic acid vaccines and formulations could protect mice from lethal influenza A/PR/8/34 (H1N1) infection. The mice used were 6-8 week old female BALB/c mice in groups of 10. Mice were vaccinated on weeks 0 and 3 via IM, ID, or IV route. Mouse serum was tested for microneutralization and HAI. Mice were then challenged with ˜1 LD₉₀ of influenza A/PR/8/34 (H1N1) on week 7 administered intranasally (IN). Endpoint was day 13 post infection, death, or euthanasia. Animals displaying severe illness as determined by >30% weight loss, extreme lethargy, or paralysis were euthanized. Temperature and weights were taken daily.

The LNP formulation consisted of a cationic lipid, non-cationic lipid, PEG lipid and structural lipid in the ratios 50:10:1.5:38.5. The cationic lipid was DLin-KC2-DMA (50 mol %), the non-cationic lipid was DSPC (10 mol %), the PEG lipid was PEG-DOMG (1.5 mol %) and the structural lipid was cholesterol (38.5 mol %).

Serum was collected from each mouse on weeks 1, 3 (pre-dose), and 5. Individual bleeds were tested for anti-HA activity via virus neutralization assay and HA inhibition (HAI) from all three time points (individual animals) and pooled samples from week 5 only were tested by Western blot using inactivated Influenza A/PR/8 (H1N1).

Standard Protocol for Intranasal Infection of Mice

Female 6-8 week old BALB/c mice were housed in groups of 5 mice. Mice were quarantined at the study site (Noble Life Sciences, Gaithersburg, Md.) for at least 3 days prior to the start of the study. Food and water was provided ad libitum.

The groups of mice challenged with INFV were infected via intranasal (IN) inoculation with ˜10×LD90 in 100 μL of INFV in PBS under light anesthesia (Isoflurane). After the infection, mice were placed back into their cages for observation and subsequent dosing.

Microneutralization

The microneutralization protocol was the standard protocol for microneutralization of influenza as published by the World Health Organzation, 6 Dec. 2010 and outlined by the WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Centers for Disease Control and Prevention, Atlanta, USA, the contents of which are incorporated herein by reference in their entirety.

Serologic Diagnosis of Influenza Virus Infections by Hemagglutination Inhibition.

The standard protocol for inhibition of hemagglutination can be found in publication WHO Influenza Manual, WHO/CDS/CSR/NCS/2002.5 Rev. 1, at page 37, the contents of which are incorporated by reference in their entirety.

Briefly, the protocol is as follows.

Procedure

-   I. Treatment of sera -   1. Identification of Influenza Isolates by Hemagglutination. -   2. Adsorb sera to remove nonspecific agglutinins as described above. -   II. Standardization of RBCs -   Standardize RBCs according to the procedure in art recognized     procedures. -   III. HA Titration of control antigens -   Following the procedure for titration of the control antigens given     above. -   IV. Preparation of standardized antigens for HAI test and “Back     Titration” -   Each control antigen must be standardized to contain 4HA units/25     μl, 8HA units/50 μl. -   Note: Four HA units are added to the test in 25 μl because the HA     unit calculations are based on a volume of 50 μl. -   V. HAI Test for serologic diagnosis -   1. Label appropriate microtiter plates. -   2. Add 25 μl of PBS to wells B through H (B1-H12) of each numbered     column. -   3. Add 50 μl of each treated serum (1:10) to the appropriate first     well (A1-A12) of the numbered column. -   4. Prepare serial twofold dilutions of the treated sera by     transferring 25 μl from the first well of the numbered columns 1-12     to successive wells. -   Discard the final 25 μl after row H. -   5. Add 25 μl of standardized antigen to all wells (A1-H12) in a set     of treated sera. -   6. Add 25 μl of PBS instead of antigen to the set of treated sera     for serum controls (A1-H12). -   7. Mix the contents of the plates by shaking on a mechanical     vibrator for 10 sec or by agitating the plates manually. -   8. Cover the plates and incubate at room temperature (22 to 25° C.)     for 30-45 min. -   9. Add 50 μl of standardized RBCs to all wells. Mix as before. -   10. Cover the plates and allow the RBCs to settle at room     temperature (22 to 25C) for the appropriate time according to RBCs     being used. -   11. Record the HAI titers.

The positive control antigens and corresponding antisera should give consistent results when compared with previous tests. A fourfold titer increase between the acute and convalescent serum is considered diagnostically positive for that influenza type/subtype.

Western Blots

Serum from bleeds performed on vaccinated mice on week 5 was pooled and diluted 1:1000 for analysis in Western blots. Inactivated PR8 antigen was separated via SDS-PAGE and probed with the pooled sera. Positive signals were observed in groups 2-7 and 12, with the highest signals observed in groups 4-7 and 12.

500 ng per lane of inactivated PR8 antigen was separated via SDS-on 10% bis-tris gels. Protein was transferred to Polyvinylidene Difluoride (PVDF) membranes and membranes were blocked with milk and probed with a 1:1000 dilution of pooled sera from each group from week 5 bleeds.

Antibody was detected with 1:3000 dilution of goat anti-mouse alkaline phosphatase (AP)

Observation of Mice

Mice were observed through 13 days post infection (14 days total, 0-13 days post infection).

Mice were weighed daily on an Ohause scale and the weights were recorded.

All animals had chips implanted at least 3 days prior to virus challenge that monitored the body temperature. The temperatures were recorded daily.

Survival and health of each mouse was evaluated once time a day.

TABLE 31 Study Design Vaccine Mouse (n = 5 mice/group) Group Strain Delivered week 0, 3 Dosage/Route Readouts 1 Female N/A N/A Animals displaying 2 BALB/c, Unmodified LNP IV, severe illness will 3 6-8 N1-methyl 0.4 mg/kg be euthanized. weeks of pseudouridine/5- Serum samples age methyl cytosine collected on weeks 4 Unmodified IM, LNP 1, 3, and 5. 5 N1-methyl 0.4 mg/kg Serum analyzed via pseudouridine/5- Western blot (week methyl cytosine 5 pooled samples), 6 Unmodified ID, LNP virus neutralization 7 N1-methyl 0.4 mg/kg assay (all pseudouridine/5- individuals), and methyl cytosine HAI (all 8 Unmodified ID, 80 ug individuals). 9 N1-methyl w/lipoplex pseudouridine/5- (Lipofectamine methyl cytosine 2000) 10 Unmodified ID, 80 ug naked 11 N1-methyl mRNA pseudouridine/5- methyl cytosine 12 Control IN, Inactivated PR8 virus

In the Table the following abbreviations apply; IM, intramuscular; ID, intradermal; IN, intranasal; IV, intraveneous; LNP, lipid nanoparticle

TABLE 32 Mean HAI Titers Sample ID Week 1 Week 3 Week 5 Naïve 8 7 7 Unmodified; LNP IV, 0.4 mg/kg 8 28 635 N1-methyl pseudouridine/ 25 139 2004 5-methyl cytosine; LNP IV, 0.4 mg/kg Unmodified; LNP IM, 0.4 mg/kg 22 63 2560 N1-methyl pseudouridine/5-methyl 60 482 2803 cytosine; LNP IM, 0.4 mg/kg Unmodified; LNP ID, 0.4 mg/kg 39 279 3796 N1-methyl pseudouridine/5-methyl 114 965 10152 cytosine; LNP ID, 0.4 mg/kg Unmodified; 80 ug w/lipoplex 7 17 197 (Lipofectamine 2000) N1-methyl pseudouridine/5-methyl 7 20 28 cytosine; 80 ug w/lipoplex (Lipofectamine 2000) Unmodified; ID, 80 ug naked mRNA 7 7 61 N1-methyl pseudouridine/5-methyl 7 16 133 cytosine; ID, 80 ug naked mRNA Control PR8 Antigen 14 14 441 Inhibition of Hemagglutination

Inhibition of hemagglutination (HAI) was measured in mouse sera samples on weeks 1, 3, and 5 post-vaccination. After week 1, both groups 5 and 7 displayed HAI titers over 40, at 60 and 114, respectively. On week 3, groups 3-7 displayed HAI activity over 40, with the highest being group 7 at 965. On week 5, all groups except 1 (naïve) and 9 displayed HAI activity over 40, with group 7>10,000.

It is noted that 1:40 is predictive of efficacy. An HAI titer of >40 is deemed necessary to protect from a lethal challenge of influenza.

The data showed that there was 100% rescue from lethal influenza challenge with rapid onset of protective antibody titers after 1 week and high antibody titers, i.e., 50 fold over unmodified mRNA and 20 fold over the protein vaccine. Furthermore, it was shown that for ribonucleic acid vaccines of the invention a much lower effective mRNA dose is required, i.e., ten fold less than unmodified mRNA. (FIG. 10).

Microneutralization

Two-fold dilutions of mouse sera were added to 100 TCID50/ml of virus in 96-well plates. After 24-hours of incubation, 1.5×104 Madin-Darby Canine-Kidney cells were added to each well. After a ˜20 hour incubation at 37° C., virus was detected and scored with an anti-NP antibody and read at 490 nm. No neutralization activity was detected with week 1 samples (signal <50; lower limit of detection). By week 3, mice in groups 5 and 7 displayed neutralizing activity between 79 and 250 (group 5) and 250 (group 7). Neither of the other groups displayed any neutralizing activity. On week 5, groups 2-4 showed high neutralizing activity between 789 and 2493, with group 7 displaying neutralizing activity 2494 and ˜25,000. The control group of mice, vaccinated with inactivated PR8, displayed neturalizing activity in 3 of 5 mice and ranged between 79 and 250. The data are shown in Tables 33-35.

TABLE 33 Week 1 Microneutralization Mouse Mouse Mouse Mouse Mouse Sample ID 1 2 3 4 5 Naïve  <50* <50 <50 <50 <50 Unmodified; LNP IV, <50 <50 <50 <50 <50 0.4 mg/kg N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; LNP IV, 0.4 mg/kg Unmodified; LNP IM, <50 <50 <50 <50 <50 0.4 mg/kg N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; LNP IM, 0.4 mg/kg Unmodified; LNP ID, <50 <50 <50 <50 <50 0.4 mg/kg N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; LNP ID, 0.4 mg/kg Unmodified; 80 ug w/ <50 <50 <50 <50 <50 lipoplex (Lipofectamine 2000) N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; 80 ug w/lipoplex (Lipofectamine 2000) Unmodified; ID, 80 ug <50 <50 <50 <50 <50 naked mRNA N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; ID, 80 ug naked mRNA Control PR8 Antigen <50 <50 <50 <50 <50 *Titers of ‘<50’ indicate titers below Limit of detection (1:50)

TABLE 34 Week 3 Microneutralization Mouse Mouse Mouse Mouse Mouse Sample ID 1 2 3 4 5 Naïve  <50* <50 <50 <50 <50 Unmodified; LNP IV, <50 <50 <50 <50 <50 0.4 mg/kg N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; LNP IV, 0.4 mg/kg Unmodified; LNP IM, <50 <50 <50 <50 <50 0.4 mg/kg N1-methyl   79 79 79 250 250 pseudouridine/5- methyl cytosine; LNP IM, 0.4 mg/kg Unmodified; LNP ID, <50 <50 <50 <50 <50 0.4 mg/kg N1-methyl 250 250 250 250 250 pseudouridine/5- methyl cytosine; LNP ID, 0.4 mg/kg Unmodified; 80 ug <50 <50 <50 <50 <50 w/lipoplex (Lipofectamine 2000) N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; 80 ug w/lipoplex (Lipofectamine 2000) Unmodified; ID, 80 ug <50 <50 <50 <50 <50 naked mRNA N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; ID, 80 ug naked mRNA Control PR8 Antigen <50 <50 <50 <50 <50 *Titers of ‘<50’ indicate titers below Limit of detection (1:50)

TABLE 35 Week 5 Microneutralization Mouse Mouse Mouse Mouse Mouse Sample ID 1 2 3 4 5 Naïve  <50* <50 <50 <50 <50 Unmodified; LNP IV, 2493  789 789 <50 250 0.4 mg/kg N1-methyl 789 789 2493 789 2493 pseudouridine/5- methyl cytosine; LNP IV, 0.4 mg/kg Unmodified; LNP IM, 789 789 2493 789 2493 0.4 mg/kg N1-methyl 789 2493 2493 789 789 pseudouridine/5- methyl cytosine; LNP IM, 0.4 mg/kg Unmodified; LNP ID, <50 <50 <50 <50 <50 0.4 mg/kg N1-methyl 7877  7877 24892 2493 7877 pseudouridine/5- methyl cytosine; LNP ID, 0.4 mg/kg Unmodified; 80 ug w/ <50 <50 <50 <50 79 lipoplex (Lipofectamine 2000) N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; 80 ug w/lipoplex (Lipofectamine 2000) Unmodified; ID, 80 ug <50 79 <50 <50 <50 naked mRNA N1-methyl <50 <50 <50 <50 <50 pseudouridine/5- methyl cytosine; ID, 80 ug naked mRNA Control PR8 Antigen 250 79 <50 <50 250 *Titers of ‘<50’ indicate titers below Limit of detection (1:50) Survival

All mice were challenged with a lethal dose (10×LD90) of INFV A/PR/8/34 on week 7 post-vaccination. Mice were observed for morbidity and mortality for up to 14 days. All vaccinated mice displayed 100% survival, compared to the naïve group (group 1), which was not vaccinated. 12 groups of 5 mice were challenged via IN instillation with ˜100 PFU of INFV A/PR/8/34 (H1N1). Mice were observed daily for 14 days for health, morbidity, and mortality. All animals except for unvaccinated, which died at approximately day 7, survived the 14 day study.

Weight Loss Data

Weight loss and health of mice challenged with A/PR/8/34. 12 groups of 5 mice were challenged via IN instillation with ˜100 PFU of INFV A/PR/8/34 (H1N1). Mice were observed daily for 14 days for health, morbidity, and mortality.

All vaccinated mice displayed 100% survival, although some groups displayed weight loss. The unvaccinated group displayed 0% survival and died on days 6 and 7, post-infection. While differences in weight-loss were observed in challenged vaccinated mice, no conclusion can be drawn as to its significance. The group vaccinated with NAVs having N1 methylpseudouridine/5-methyl cytosine with naked mRNA displayed health scores of ‘2’ on days 2 and 3 post-infection, but made a recovery to ‘healthy’ for the rest of the study. The groups vaccinated with NAVs having N1 methylpseudouridine/5-methyl cytosine ID 80 ug w/lipofecatmine 2000 (LF2000) and Nlmethylpseudouridine and 5-methylcytosine LNP ID both displayed health scores of ‘2’ on days 5 and 6 post-infection which continued through the duration of the study. The LNP formulation consisted of a cationic lipid, non-cationic lipid, PEG lipid and structural lipid in the ratios 50:10:1.5:38.5. The cationic lipid was DLin-KC2-DMA (50 mol %), the non-cationic lipid was DSPC (10 mol %), the PEG lipid was PEG-DOMG (1.5 mol %) and the structural lipid was cholesterol (38.5 mol %).

All groups generally maintained weight between 90-110% of original weight with the exception of the unvaccinated group. These animals were at approximately 70% of their original weight by day 6. Health scoring was per Table 36.

TABLE 36 Health score chart Score Initial Description Appearance Mobility Attitude 1 H Healthy Smooth coat, bright eyes Active, scurrying, Alert burrowing 2 SR Slighly Slightly ruffled coat Active, scurrying, Alert Ruffled (usually only around heand burrowing and neck 3 R Ruffled Ruffled coat throughout Active, scurrying, Alert body. A “wet” appearance burrowing 4 S Sick Verr ruffled coat. Slightly Walking, but not Mildly closed, inset eyes scurrying lethargic 5 VS Very Sick Very ruffled coat, closed, Slow to no movement; Extremely (euthanized) inset eyes will return upright lethargic position if put on side 6 E Euthanize Very ruffled coat, closed No movement or Completely inset eyes; moribund uncontrollable; spastic unaware or requires human euthenasia movement. Will not in noticeable return to upright distress 7 D Deceased — — —

Example 16 MRSA Study

Antigens of MRSA which may be encoded by the ribonucleic acid vaccines include, SpA, SpAKKAA, IsdA, IsdB, SDRD, SDRE, TSST-1, PVL, a-HL, NMD-1 and SCCmec. The study design is shown in Table 37. In these studies, construct number 27 from Table 28 was used.

A. Test for Efficacy of Modified Ribonucleic Acid Vaccines in Staph. Aureus Pneumonia Challenge Model in Mice

This study will test the efficacy of ribonucleic acid vaccine encoding MRSA Ag808 in BALB/c mice. The study utilizes 15 groups of 15 BALB/c female mice (225 total. Mice are vaccinated on week 0 and 3 via intradermal (ID) or intramuscular (IM) route with either an LNP Formulation comprising DLin-KC2-DMA (“KC2”) or DLin-MC3-DMA (“MC3”). The KC2 LNP formulation consisted of a cationic lipid (DLin-KC2-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). The MC3 LNP formulation consisted of a cationic lipid (DLin-MC3-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). One group is unvaccinated and one administered a positive control antigen. Prior to challenge, mice will be bled by tail vein on weeks 1, 3 and 5 and serum samples will be retained for later analysis. The mice will be challenged with MRSA (strain Newman) at ˜1×LD90 via intranasal (IN) inoculation on week 5. Mice will be monitored for morbidity using a health score assigned based on a standard scoring system, weight loss, and mortality and the endpoint is day 14 post infection, death, or euthanasia. Animals displaying severe illness as determined by >30% weight loss, extreme lethargy, or paralysis will be euthanized. Mice will be held until week 7, to perform additional work with the animals (ex. further vaccinations, bleed or infectious challenge).

B. Test for Efficacy of N1-methylpseudouridine Modified Ribonucleic Acid Vaccines in Staphylococcus aureus Peritonitis Challenge

This study tested the efficacy of a ribonucleic acid vaccine encoding MRSA Ag808 in BALB/c mice. The study utilized 15 groups of 15 BALB/c female mice (270 total. Mice were vaccinated on week 0 and 3 via intradermal (ID) or intramuscular (IM) route with either an LNP Formulation comprising DLin-KC2-DMA (“KC2”) or DLin-MC3-DMA (“MC3”). The KC2 LNP formulation consisted of a cationic lipid (DLin-KC2-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). The MC3 LNP formulation consisted of a cationic lipid (DLin-MC3-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). One group was unvaccinated and one administered a positive control antigen. Prior to challenge, mice were bled by tail vein on weeks 1, 3 and 5 and serum samples were retained for later analysis. The mice that were challenged via intranasal instillation received a predicted challenge dose of 2e8 CFU/mouse (actual upon back-titration was 3.3e8/mouse) and the mice that were challenged via IP infection received a predicted 1e7 CFU/mouse (actual upon back-titration 6.7e6 CFU/mouse). Mice were monitored for morbidity using a health score assigned based on a standard scoring system, weight loss, and mortality and the endpoint is day 14 post infection, death, or euthanasia. Animals displaying severe illness as determined by >30% weight loss, extreme lethargy, or paralysis were euthanized.

TABLE 37 Study Design Group (n = 15) Antigen Dosage Route Chemistry Formulation Administration Samples 1 N/A N/A N/A N/A NaCl Vaccination on Bled by 2 MRSA 0.4 mg/kg ID N1methyl- LNP; KC2 weeks 0 and 3 tail vein 3 Ag808 0.08 mg/kg pseudoruridine on weeks 4 0.016 mg/kg 1, 3, and 5; 5 0.4 mg/kg IM retained 6 0.08 mg/kg for future 7 0.016 mg/kg analysis 8 0.4 mg/kg ID LNP; MC3 9 0.08 mg/kg 10 0.016 mg/kg 11 0.4 mg/kg IM 12 0.08 mg/kg 13 0.016 mg/kg 14 Inactivated TBD TBD N/A TBD bacteria 15 Inactivated TBD TBD N/A TBD bacteria

Mice that were vaccinated and challenged via IP route with 3% hog mucin all displayed 0% survival within 24 hours of challenge. Mice that were vaccinated and challenged via IN instillation displayed between 6 and 33% survival and median survival times between 2 and 3 days. Efficacy was not shown with either the tested RNA vaccine construct or the controls (inactivated bacteria and protein control) in either challenge model, suggesting that the model was not adequate for testing the constructs. The vehicle-vaccinated group displayed 20% survival and a median survival time of 3 days. Without being bound in theory, is is believed that the severity of the MRSA infection model precluded detection of vaccine efficacy. Other models can be tested to determine efficacy.

Example 17 Dengue Study: Dengue Virus RNA Vaccine Immunogenicity in Mice

This study provides a preliminary analysis of the immunogenicity of a nucleic acid mRNA vaccine using a dengue virus (DENV) serotype 2 antigen in BALB/c mice. The study utilizes 44 groups of 10 BALB/c female (5) and male (5) mice (440 total, 6-8 weeks of age at study initiation, see Table38 for design summary). In this study, construct numbers used are referenced and found in Table 28.

Mice were vaccinated on weeks 0 and 3 via intramuscular (IM) or intradermal (ID) routes. One group remained unvaccinated and one was administered 10⁵ plaque-forming units (PFU) live DENV2, D2Y98P isolate via intravenous (IV) injection as a positive control. Serum was collected from each mouse on weeks 1, 3, and 5; bleeds on weeks 1 and 3 were in-life samples (tail vein or submandibular bleeds) and week 5 will be a terminal (intracardiac) bleed. Individual serum samples were stored at −80° C. until analysis by neutralization or microneutralization assay. Pooled samples from each group at the week 5 time points were tested by Western blot for reactivity with viral lysate.

TABLE 38 Detailed experimental design (treatment, readouts) Vaccine (n = 10, female) mice/group) Mouse Delivered Formulation/ Group Strain week 0 and 3 Chemistry Route Dose Readouts 1 Female N/A N/A N/A Serum samples 2 BALB/ DEN2Y98- N1- ID 0.4 mg/kg in LNP collected on 3 c, 6-8 PrME methylpseudouridine/ IM weeks 1, 3, 4 weeks (construct 5-methyl cytosine ID 0.08 mg/kg in LNP and 5. 5 of age 23 from IM Serum 6 Table 28) ID 0.016 mg/kg in LNP analyzed via 7 IM Western blot 8 N1- ID 0.4 mg/kg in LNP 9 methylpseudouridine IM 10 ID 0.08 mg/kg in LNP 11 IM 11 ID 0.016 mg/kg in LNP 12 IM 13 DEN2Y98- N1- ID 0.4 mg/kg in LNP 14 PrME80 methylpseudouridine/ IM 15 (construct 5-methyl cytosine ID 0.08 mg/kg in LNP 16 24 from IM 17 Table 28) ID 0.016 mg/kg in LNP 18 IM 19 N1- ID 0.4 mg/kg in LNP 20 methylpseudouridine IM 21 ID 0.08 mg/kg in LNP 22 IM 23 ID 0.016 mg/kg in LNP 24 IM 25 DEN2Y98- N1- ID 0.4 mg/kg in LNP 26 PrME80-DC methylpseudouridine/ IM 27 (construct 5-methyl cytosine ID 0.08 mg/kg in LNP 28 25 from IM 29 Table 28) ID 0.016 mg/kg in LNP 30 IM 31 N1- ID 0.4 mg/kg in LNP 32 methylpseudouridine IM 33 ID 0.08 mg/kg in LNP 34 IM 35 ID 0.016 mg/kg in LNP 36 IM 37 DEN2-DIII- N1- ID 0.4 mg/kg in LNP 38 Ferritin methylpseudouridine IM 39 (construct ID 0.08 mg/kg in LNP 40 18 from IM 41 Table 28) ID 0.016 mg/kg in LNP 42 IM 43 Control, — IV 10⁵ PFU D2Y98P live virus

Signal was detected in groups 5, 15, 39, and 44 (live virus control) by a band that appeared between 50 and 60 kDa in the Western blot data. The data suggests that a mRNA vaccine to a single dengue viral antigen can produce antibody in preliminary studies.

Example 18 Tuberculosis Ribonucleic Acid Vaccine: Combinatorial Approach of Adjuvants and Antigens

The objective of the study is to identify a multi-valent, multi-adjuvant vaccine effective in different diseases stages of tuberculosis. Initial experiment assesses 12 antigens with 8 cytokine adjuvants in three disease stage models. The antigens encoded by the polynucleotides of the invention include Ag85A (Rv3804c), Ag85B (Rv1886c), TB10.4 (Rv0288), ESAT6 (Rv3785), Rv2660L, Rv3619, Rv1813c, Rv3620c, Rv2608, Rv1196, Rv0125 and/or MT401. Target cytokine adjuvants include GM-CSF, IL-17, IFNg, IL-15, IL-2, IL-21, Anti-PD1/2 and/or Lactoferrin.

Example 19 Human Enterovirus (HEV68 and HEV71) Study

Several key antigens for use in generating vaccines have been identified. These include: (i) VP1 BC/DE loop of all three HEV68 lineages and (ii) VP1+VP2 of HEV71. The RNAV polynucleotide for use in generating vaccines from the HEV71 antigen is construct 72 from Table 28).

Example 20 MERS-CoV Study

As MERS-CoV binds cells via DPP4Fc, treatment for MERS-CoV can include an mRNA encoding DPP4-Fc with or without MERS-CoA binding site and mutant binding sites for diabetes signaling and truncated receptor binding domain of MERS-CoV Spike protein. See PLoS One. 2013; 8(12): e81587). This vaccine would act as a decoy for the virus as it will attract the MERS-CoV.

Another key vaccine for MERS-CoV is identified as an mRNA encoding MERS-CoV Spike Glucoprotein as an antigen. The protein sequence is given here (SEQ ID NO: 962).

SEQ ID NO. 962: mihsvfllmflltptesyvdvgpdsiksacievdiqqtffdktwprpidv skadgiiypqgrtysnitityqglfpyqgdhgdmyvysaghatgttpqkl fvanysqdvkqfangfvvrigaaanstgtviispstsatirkiypafmlg ssvgnfsdgkmgrffnhtlvllpdgcgtllrafycileprsgnhcpagns ytsfatyhtpatdcsdgnynrnaslnsfkeyfnlrnctfmytynitedei lewfgitqtaqgvhlfssryvdlyggnmfqfatlpvydtikyysiiphsi rsiqsdrkawaafyvyklqpltflldfsvdgyirraidcgfndlsqlhcs yesfdvesgvysvssfeakpsgsvveqaegvecdfspllsgtppqvynfk rlvftncnynltkllslfsvndftcsqispaaiasncysslildyfsypl smksdlsvssagpisqfnykqsfsnptclilatvphnlttitkplkysyi nkcsrllsddrtevpqlvnanqyspcvsivpstvwedgdyyrkqlspleg ggwlvasgstvamteqlqmgfgitvqygtdtnsvcpklefandtkiasql gncveyslygvsgrgvfqnctavgvrqqrfvydayqnlvgyysddgnyyc lracvsvpvsviydketkthatlfgsvacehisstmsqysrstrsmlkrr dstygplqtpvgcvlglvnsslfvedcklplgqslcalpdtpstltprsv rsvpgemrlasiafnhpiqvdqlnssyfklsiptnfsfgvtqeyiqttiq kvtvdckqyvcngfqkceqllreygqfcskinqalhganlrqddsvrnlf asvkssqsspiipgfggdfnltllepvsistgsrsarsaiedllfdkvti adpgymqgyddcmqqgpasardlicaqyvagykvlpplmdvnmeaaytss llgsiagvgwtaglssfaaipfaqsifyrlngvgitqqvlsenqkliank fnqalgamqtgftttneafhkvqdavnnnagalsklaselsntfgaisas igdiiqrldvleqdaqidrlingrlttlnafvaqqlvrsesaalsaqlak dkvnecvkaqskrsgfcgqgthivsfvvnapnglyfmhvgyypsnhievv sayglcdaanptnciapvngyfiktnntrivdewsytgssfyapepitsl ntkyvapqvtyqnistnlpppllgnstgidfqdeldeffknvstsipnfg sltqinttlldltyemlslqqvvkalnesyidlkelgnytyynkwpwyiw lgfiaglvalalcvffilcctgcgtncmgklkcnrccdryeeydlephkv hvh

Example 21 H10N8 In Vitro Studies

In vitro studies on the translatability of H10 hemagglutinin mRNA were performed in HeLa cells.

Western blot analysis revealed that HA is expressed in HeLa cells following transfection with the mRNA NAV encoding the HA protein of the H10N8 strain of influenza virus.

Example 22 Influenza Study—Dosing and Formulations

A mRNA vaccine encoding the HA protein of the H1N1 strain of influenza virus was tested at various doses and in various formulations for the ability ti illicit an immune response in mice.

The efficacy of different doses and formulations were evaluated in mice. HAI titers of mice determined on Day 35 after vaccination on Day 0 and Day 21 with mRNA encoding HA of the H1N1 virus are shown in FIG. 11. Titers were highest at doses of 10 μg mRNA/mouse (400 μg mRNA/kg) with both the KC2 and MC3 formulations administered ID or IM (Table 39).

TABLE 39 Hemagglutinin inhibition titers in mice following vaccination with different doses and formulations of mRNA encoding the hemagglutinin protein of the H1N1 virus vaccine Route of Group No. Vaccination on Dose Mean HAI (n = 10 per group) days 0 and 21 Vaccine Formulation (μg/mouse) titer ± SD 1 N/A None PBS 0 0 2 ID H1N1/C1 KC2 10 1792 ± 661  3 2 1088 ± 309  4 0.4 272 ± 152 5 0.08 52 ± 44 6 ID H1N1/C0 KC2 10 992 ± 648 7 2 692 ± 743 8 0.4 140 ± 78  9 0.08 35 ± 31 10 ID H1N1/C0 MC3 10 1600 ± 867  11 2 1152 ± 588  12 0.4 290 ± 254 13 0.08 37 ± 25 14 IM H1N1/C0 MC3 10 1664 ± 1422 15 2 1056 ± 641  16 0.4 800 ± 346 17 0.08 180 ± 105 18 IN Inactivated PBS 20 μL 96 ± 47 PR8 virus 19 ID H1N1/G2/C1 PBS 50 11 ± 3  G0 = generation 0, i.e. canonical unmodified nucleotides; G2 = Generation 2 of the modified nucleotides; G5 = Generation 5 of the modified nucleotides (intended for clinical development). C0 = CAP0; C1 = CAP1 (intended for clinical development) N/A: Not applicable. IN: intranasal: ID: intradermal; IM: intramuscular

Example 23 Influenza Study—Onset of Immunity—Survival and HAI

This study evaluated the efficacy of an mRNA vaccine encoding influenza A/PR/8 (H1N1) in female BALB/c mice following lethal challenge with influenza A/PR/8 virus. Groups of animals were vaccinated and challenged after week 1, 2, 3, or 4. Serum was collected from each mouse one day prior to challenge. Individual bleeds were tested for hemagglutination inhibition using Influenza A/PR/8 (H1N1). Control groups included unvaccinated mice and mice vaccinated with inactivated PR8 virus as a positive control. These animals were challenged in parallel with groups that were vaccinated with the mRNA vaccine. Challenge was performed with a lethal dose (100 PFU) of A/PR/8/34 (H1N1) via intranasal instillation. Animals were monitored for morbidity using a health score assigned based on a standard scoring system, weight loss and mortality. All mice receiving the mRNA vaccine showed 100% survival and minimal body weight loss (FIG. 12A-12D). At week 1 post vaccination, hemagglutination inhibition titers of mice receiving the mRNA vaccine and mice receiving the positive control vaccine were similar. However, at weeks 2, 3 and 4 post vaccination, mice receiving the mRNA vaccine showed higher mean titers compared with mice receiving the positive control vaccine (FIG. 13).

Groups of 15 female BALB/c mice (6-8 weeks of age) were vaccinated in week 0 with: mRNA encapsulated in LNP at a dose of 0.4 mg/kg by ID injection; inactivated PR8 virus given IN; or vehicle.

In weeks 1, 2, 3 and 4 after vaccination, animals were inoculated with influenza A/PR/8/34 virus under light anesthesia. The animals received 100 μL of the virus diluted in PBS to a final concentration of 1×103 PFU/mL via IN instillation.

Health assessments were performed and weights were recorded daily for 14 days (days 0-13 post infection). Survival and health was evaluated using the scoring system shown in Table 36.

All animals had chips implanted at least 3 days prior to virus challenge that monitored the body temperature. The temperatures were recorded daily. One day prior to each challenge, serum samples were collected and the serum was analyzed in an HAI assay.

Survival curves are presented in FIG. 15. The animals were monitored for survival for 14 days. Log-rank analysis was performed in GraphPad Prism v6.

Mice vaccinated with mRNA vaccine or inactivated PR8 all displayed 100% survival, while mice that were unvaccinated displayed between 0 and 40% survival (Table 40.) No significant decreases in body weight of treated mice were detected.

TABLE 40 Percent and mean survival of mice after vaccination and challenge with influenza A/PR/8/34 virus Significance to Relative Mean Vehicle Group Survival Control (n = 15 per group) % Survival (Days) (p values) Vehicle Week 1 10 8 N/A Week 2 40 10 N/A Week 3 0 9 N/A Week 4 6.67 9 N/A Inactivated Week 1 100 Undefined <0.0001 PR8 virus Week 2 100 Undefined 0.0004 Week 3 100 Undefined <0.0001 Week 4 100 Undefined <0.0001 mRNA vaccine Week 1 100 Undefined <0.0001 encapsulated Week 2 100 Undefined 0.0004 in LNP Week 3 100 Undefined <0.0001 Week 4 100 Undefined <0.0001

Mean HA titers are shown in FIG. 13 and Table 41.

TABLE 41 Mean hemaglutination inhibition (±SD) titers of mice after vaccination and challenge with influenza A/PR/8/34 virus Vaccination Challenge with influenza A/PR/8/34 virus in week 0 Week 1 Week 2 Week 3 Week 4 Vehicle 0 0 0 0 Inactivated PR8 virus 25 ± 47 19 ± 26 37 ± 39 43 ± 30 mRNA vaccine 25 ± 17 203 ± 138 379 ± 178 363 ± 154 Values are mean ± SD (standard deviation)

These data demonstrate that mice vaccinated with mRNA vaccine at a dose of 0.4 mg/kg ID or inactivated PR8 virus showed 100% survival after challenge with influenza A/PR/8/34 virus in weeks 1, 2, 3, or 4 indicating that the vaccine conveyed protection against infection with influenza A/PR/8/34 virus under the conditions of this study. HAI activity remained low in weeks 1 through 4 for animals vaccinated with inactivated PR8 virus. Mice vaccinated with mRNA showed low mean HAI titers in week 1 after challenge, but increased titers in weeks 2, 3 and 4, respectively.

Example 24 Evaluation of H1 and H7-Specific T Cell Responses in Influenza Vaccine

Mice were immunized ID at week 0 and 3 with mRNA vaccine encoding the HA protein of influenza H1N1 or H7N9 virus and splenocytes were collected in week 5. T cells were stimulated for 16-18 hours with an HA peptide library (15mers of a full length protein)

that reproduce the H1 or H7 sequence. Non-specific stimulation of T cells was performed using PMA+ionomycin. IFNγ ELISpot was used to identify staining for IFNγ. B cells were stimulated with either a peptide library (15mers of a full length protein) that reproduce the H1 or H7 sequence. Polyclonal B cell stimulation was performed using R848+rIL-2. B cell ELISpot was used to identify staining for antigen-specific IgG.

IFNγ ELISpot results demonstrated increased IFNγ secretion by T cells after stimulation with H1 or H7 peptides (FIGS. 14A and 14B). No increased IFNγ secretion was observed in T cells stimulated with PMA+ionomycin (FIG. 14C). The results demonstrated that T cell responses are antigenspecific.

B cell ELISpot results demonstrated IgG secretion upon stimulation of B cells with full antigen, but not with H1/H7 peptides (FIGS. 15A-15D). The lack of stimulation with the peptide library was to be expected because an IgG response is stimulated via MHCII antigens, which tend to be longer than MHCI antigen needed for stimulation of a T cell response.

Example 25 Evaluation of H1, H7, and MO-Specific T and B Cell Response Against Influenza Vaccines in Mouse Splenocytes

Influenza-specific T and B cell responses were evaluated following administration of mRNA vaccines (NAVs) encoding the H1, H10, and H7 hemagglutinin proteins. Briefly, 36 groups of 5 female 6-8 week old BALB/c mice were vaccinated with various doses via the intradermal route (ID) on day 0. Seven-week post vaccination, nimals were sacrificed and spleens were harvested. The splenocytes were assessed by IFNγ ELISpot; Intracellular Cytokine Staining (ICS) for CD3, CD4, CD8, CD45, CCR7, CD44, CD25, IL-2 IFNγ, and TNFα markers; and by B-cell ELISpot.

IFNγ ELISpot Analyses

Splenocytes from groups of mice that had been administered H10N8/N1-methyl pseudouridine/C0 were assessed for H1, H7 and H10-specific IFNγ production by IFNγ ELISpot. Naïve mice did not yield measurable IFNγ cytokine response, whereas H10 peptide-specific IFNγ ELISpot responses were detected in mice vaccinated intradermally with H10N8/N1-methyl pseudouridine /C0. The magnitude of these responses was found to be dependent on the dose of the vaccine administered. Peptide-stimulated splenocytes did not yield detectable H1- or H7-specific IFNγ ELISpot responses. All groups produced IFNγ ELISpot responses following stimulation with PMA+ionomycin (positive control).

H1 peptide-specific IFNγ ELISpot responses were detected from splenocytes isolated from mice that had been administered H1N1/G2/C1, H1N1/G2/C0 (MC3 formulation), or H1N1/G2/C0 (KC2 formulation) intradermally, as well as from splenocytes from mice that had been administered H1N1/G2/C0 (MC3 formulation) intramuscularly.

H7 peptide-specific IFNγ ELISpot responses were detected from splenocytes isolated from mice that had been administered H7N9/G2/C0 either intradermally or intramuscularly.

Splenocytes from control mice that had received H1N1/G2/C1/PBS showed no response to peptide stimulation.

B Cell ELISpot Analyses

Briefly, H1-specific IgG and IgM responses were detected in several groups of mice vaccinated with different H1 vaccine formulations. H7- and H10-specific IgG and IgM responses were also elicited in the H7N9/N1-methyl pseudouridine /C0- and H10N8/N1-methyl pseudouridine /C0-vaccinated mice, respectively.

Intracellular Cytokine Staining Results

Intracellular Cytokine Staining and flow cytometric analysis indicated that H1-specific Th1 (IFNγ, TNFα, IL-2) cytokine responses were induced at both 16-18 hrs and 48 hrs in CD4+ T cells and CD8+ T cells following stimulation of splenocytes from H1-vaccinated mice with corresponding peptide or protein.

Additionally, H7- and H-10 peptide and protein-specific Th1 (IFNγ, TNFα, IL-2) responses were also detected in CD4+ and CD8+ T cells. H7-specific responses were noted in groups vaccinated with H7 vaccine formulations, and H10-specific responses were seen in groups vaccinated with H10 vaccine formulations.

Example 26 Evaluation of H7- and MO-Specific T and B Cell Response Against Influenza Vaccines in Mouse Splenocytes—Time Course

Influenza-specific T and B cell responses were evaluated following administration of mRNA vaccines (NAVs) encoding the H10 and H7 hemagglutinin proteins. Briefly, 27 groups of 5 female 6-8 week old BALB/c mice (135 mice total) were vaccinated with various doses via the intradermal route (ID) on day 0 shown in Table 42. On days 7, 21, and 84 groups of 5 animals were sacrificed and blood samples and spleens were harvested.

The mouse spleens were analyzed using IFNγ ELISPOT, IgG ELISPOT (for B cell responses), and Intracellular Cytokine Staining (ICS). Serum samples were analyzed for inhibition of hemagglutin (HAI) by first treating with Receptor Destroying Enzyme (RDE) to inactivate non-specific inhibitors of hemagglutination (false positives) present in the sera. Next, RDE-treated sera were adsorbed using red blood cells (RBCs) to remove non-specific agglutinin (false negatives). Serially-diluted treated sera (2-fold dilutions) were pre-incubated with a standardized quantity of recombinant influenza antigen before RBCs were added to the mixture. Inhibition of hemagglutination indicates the presence of HA-specific antibodies. Pooled anti-H10 mouse serum was used as a positive control and showed HAI titers within range of previously-observed data.

After receiving a single dose of the mRNA NAVs on day 0, HAI titers were not detected at day 7 (Table 42) but were detected at day 21 (Table 43) and continued to increase through day 84 (Table 44). Day 84 titers were 2-fold to 15-fold higher than those from day 21 (FIGS. 15 and 16).

Administration of the H10N8/N1-methyl pseudouridine /C1 formulation MC3 resulted in higher HAI titers as compared to the HAI titers induced by the H10N8/N1-methyl pseudouridine/CO formulation MC3 (FIG. 17). The MC3 LNP formulation consisted of a cationic lipid (DLin-MC3-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %).

Administration of the H10N8/N1-methyl pseudouridine/C1 formulation MC3 at 10 μg/dose achieved the highest HAI titers, whereas the HAI titers following administration of the 2.0 μg/dose and 0.4 μg/dose are similar to each other (FIG. 16).

TABLE 42 HAI Titers against H10 and H7 at Day 7 HAI titers of mouse sera mRNA vaccine Day 0 (Nov. 10, 2014) = vaccination day 0 once at day 0 Dose per Group Day 7 (Nov. 17, 2014) = terminal bleeds groups 1-9 via ID injection mouse (μg) (N = 5) M1 M2 M3 M4 M5 Mean Stdev H10N8/N1-methyl 10 1 <10 <10 <10 <10 <10 < 10 N/A HAI titers pseudouridine/C1, 2 2 <10 <10 <10 <10 <10 < 10 N/A against H10 formulation MC3 0.4 3 <10 <10 <10 <10 <10 < 10 N/A protein H10N8/N1-methyl 10 4 <10 <10 <10 <10 <10 < 10 N/A pseudouridine/C0, 2 5 <10 <10 <10 <10 <10 < 10 N/A formulation MC3 0.4 6 <10 <10 <10 <10 <10 < 10 N/A PBS 0 7 <10 <10 <10 <10 <10 < 10 N/A PBS 0 7 <10 <10 <10 <10 <10 < 10 N/A HAI titers H7N9/C0 10 8 <10 <10 <10 <10 <10 < 10 N/A against H7 H7N9/C1 10 9 <10 <10 <10 <10 <10 < 10 N/A protein

TABLE 43 HAI Titers against H10 and H7 at Day 21 HAI titers of mouse sera mRNAna vaccine Day 0 (Nov. 10, 2014) = vaccination day 0 once at day 0 Dose per Group Day 21 (Dec. 1, 2014) = terminal bleeds group 10-18 via ID injection mouse (μg) (N = 5) M1 M2 M3 M4 M5 Mean Stdev H10N8/N1-methyl 10 10 160 320 640 80 160 272 223 HAI titers pseudouridine/C1, 2 11 40 80 40 80 160 80 49 against H10 formulation MC3 0.4 12 80 160 40 80 80 88 44 protein H10N8/N1-methyl 10 13 160 40 80 20 40 68 56 pseudouridine/C0, 2 14 20 20 10 10 20 16 5 formulation MC3 0.4 15 20 10 40 20 80 34 28 PBS 0 16 <10 <10 <10 <10 <10 < 10 N/A PBS 0 16 <10 <10 <10 <10 <10 < 10 0 HAI titers H7N9/C0 10 17 40 10 10 20 20 26 13 against H7 H7N9C1 10 18 160 160 160 320 80 176 88 protein

TABLE 44 HAI Titers against H10 and H7 at Day 84 HAI titers of mouse sera mRNA vaccine Day 0 (Nov. 10, 2014) = vaccination day 0 once at day 0 Dose per Group Day 84 (Feb. 2, 2015) = terminal bleeds groups 19-27 via ID injection mouse (μg) (N = 5) M1 M2 M3 M4 M5 Mean Stdev H10N8/N1-methyl 10 19 160 320 320 1280 640 544 447 HAI titers pseudouridine/C1, 2 20 320 320 640 160 320 352 175 against H10 formulation MC3 0.4 21 640 320 160 320 640 416 215 protein H10N8/N1-methyl 10 22 160 320 320 320 320 288 72 pseudouridine/C0, 2 23 320 320 160 80 320 240 113 formulation MC3 0.4 24 40 320 320 320 80 216 143 PBS 0 25 <10 <10 <10 <10 <10 < 10 N/A PBS 0 25 <10 <10 <10 <10 <10 < 10 N/A HAI titers H7N9/C0 10 26 20 40 80 20 <10 ≤ 40 28 against H7 H7N9/C1 10 27 640 320 320 160 80 304 215 protein

Example 27 Anti-H10Hemagglutinin Analysis in Non-Human Primates—Dose Range Study

Groups of cynomoglus monkeys were vaccinated with various doses of NAV encoding H10HA/LNP formulations (50 μg/dose, 200 μg/dose, 400 μg/dose), NAV encoding H10HA/LNP delivered with 3M device, or control NAV encoding H10 HA/PBS. Serum samples were taken from the monkeys weekly and evaluated for inhibition of hemagglutinin (Table 45, FIG. 19).

TABLE 45 HAI titers against H10 protein HAI titers against H10 protein (A/Jiangxi-Donghu/346/2013) Cynomolgus Pre- Week Week Week Week Week Week Week monkey ID treatment 1 2 3 4 5 6 9 Group 1 1001 10 40 20 20 320 1280 1280 5120 (50 μg) 1002 20 20 40 40 640 2560 2560 10240 1003 <10 <10 40 80 640 2560 2560 10240 Mean <13 <23 33 47 533 2133 2133 8533 Group 2 2001 <10 <10 10 40 640 5120 2560 10240 (200 μg) 2002 20 20 20 40 640 2560 2560 10240 2003 <10 40 20 40 320 5120 5120 10240 Mean <13 <23 17 40 533 4267 3413 10240 Group 3 3001 20 <10 40 80 1280 5120 10240 20480 (400 μg) 3002 <10 40 40 160 640 5120 5120 20480 3003 <10 20 80 160 1280 10240 20480 40960 Mean <13 <23 53 133 1067 6827 11947 27307 Group 4 4001 <10 40 <10 20 40 80 80 160 (vaccine 4002 <10 40 <10 <10 40 160 160 160 device) 4003 20 40 <10 10 40 80 80 160 Mean <13 40 <10 <13 40 107 107 160 Group 5 5001 <10 20 80 320 1280 5120 5120 10240 (PBS) 5002 <10 20 40 160 1280 5120 5120 10240 5003 <10 40 40 80 1280 5120 5120 20480 Mean <10 27 53 187 1280 5120 5120 13653 Assay Positive Control: Assay Positive Control: Anti-H10 Pool of 9 mouse Anti H-10 Pool of 9 mouse sera M1, M2, M3, of sera M1, M2, M3 of Group 1, N1-methyl Group 1, N1-methyl pseudouridine (m¹ψ) pseudouridine (m¹ψ) and 5-methyl cytidine, and 5-methyl cytidine, Group 3 of study day 14 Group 3 of study day 14 HAI titer = 160 HAI titer = 80

Example 28 Determination of Time to Onset of Immunity Using an H7N9 Vaccine in a Ferret Model

The time to onset of immunity (as measured by antibody titers and reduction in viral titers following challenge) of an influenza A/Anhui/1/2013 (H7N9) vaccine was evaluated in a ferrets model of influenza infection. Briefly, twenty groups of 8 ferrets each were vaccinated on day 0 with the H7N9 mRNA NAV vaccine at a dose of 10 μg, 50 μg, or 200 μg, a vH7N9 vaccine lacking the 14 kDa cap at a dose of 200 μg, or PBS control via the intradermal route. Five of the 20 groups received a second vaccination (a booster) to determine if a second dose increased protection. The animals were then exposed to influenza A/Anhui/1/2013 (H7N9) virus via the intranasal route. The study design is shown in Table 45:

TABLE 45 Study Design Group Day of No. of Day of Day of No. Vaccine Dose Vaccination Animals Challenge Blood Draws 1 H7N9/N1-methyl pseudouridine/ 0 8 7 0, 7  C1/MC3, 200 μg 2 H7N9/N1-methyl pseudouridine/ 0 8 7 0, 7  C1/MC3, 50 μg 3 H7N9/N1-methyl pseudouridine/ 0 8 7 0, 7  C1/MC3, 10 μg 4 PBS 0 8 7 0, 7  5 H7N9/MC3 (−14 kDa Cap) 200 μg 0 8 7 0, 7  6 H7N9/N1-methyl pseudouridine/ 0 8 21 0, 21 C1/MC3, 200 μg 7 H7N9/N1-methyl pseudouridine/ 0 8 21 0, 21 C1/MC3, 50 μg 8 H7N9/N1-methyl pseudouridine/ 0 8 21 0, 21 C1/MC3, 10 μg 9 PBS 0 8 21 0, 21 10 H7N9/MC3 (−14 kDa Cap) 200 μg 0 8 21 0, 21 11 H7N9/N1-methyl pseudouridine/ 0 8 49 0, 49 C1/MC3, 200 μg 12 H7N9/N1-methyl pseudouridine/ 0 8 49 0, 49 C1/MC3, 50 μg 13 H7N9/N1-methyl pseudouridine/ 0 8 49 0, 49 C1/MC3, 10 μg 14 PBS 0 8 49 0, 49 15 H7N9/MC3 (−14 kDa Cap) 200 μg 0 8 49 0, 49 16 H7N9/N1-methyl pseudouridine/ 4, 25 8 53 4, 25, 53 C1/MC3, 200 μg 17 H7N9/N1-methyl pseudouridine/ 4, 25 8 53 4, 25, 53 C1/MC3, 50 μg 18 H7N9/N1-methyl pseudouridine/ 4, 25 8 53 4, 25, 53 C1/MC3, 10 μg 19 PBS 4, 25 8 53 4, 25, 53 20 H7N9/MC3 (−14 kDa Cap) 200 μg 4, 25 8 53 4, 25, 53

Because H7N9 does not induce a lethal disease in ferrets, the primary endpoint was viral burden in tissues (primarily lung) 3 days post-challenge, as determined by TCID50 (50% tissue culture infective dose). In addition to viral titers, blood was collected prior to vaccination and immediately prior to challenge to determine influenza-specific antibody titers, as determined by hemagglutination inhibition (HAI) and microneutralization (MN) assays.

The lung homogenate data show that a single vaccination at any concentration resulted in a reduction in viral titers, with a time to onset of immunity before 7 days post vaccination (Table 46). There was a 1 log reduction in all vaccine groups challenged 7 days post vaccination. This improved for groups challenged 21 days post vaccination in a dose-dependent fashion to 3, 2, and 1 log reduction for the 200-, 50-, and 10-μg groups, respectively (FIG. 20). This further improved for groups challenged 49 days post vaccination to 4, 2, and 3 log reduction for the 200, 50-, and 10-μg groups, respectively. A statistically significant difference was observed relative to PBS control group at 7 days post vaccination in the 10- and 200-μg groups (p<0.05). The 50-μg dose group also tended towards reduced lung viral titers, but only had statistically significant differences from the PBS group when a boost was administered. This was likely due to the occasional outlying high viral titer sample, which increased the variability in this group.

TABLE 46 Virus Burden (TCID50 Group Geographic Means) Nasal Wash Lung Homogenate Day 7 Day 21 Day 49 Day 7 Day 21 Day 49 H7N9/N1-methyl pseudouridine/ 3.7 × 10³ 3.1 × 10³ 3.3 × 10⁴ 3.0 × 10³ 4.6 × 10¹ 8.0 × 10⁰ C1/MC3 200 μg H7N9/N1-methyl pseudouridine/ 2.4 × 10³ 1.6 × 10⁴ 6.7 × 10⁴ 2.0 × 10³ 5.9 × 10² 9.7 × 10² C1/MC3 50 μg H7N9/N1-methyl pseudouridine/ 3.7 × 10³ 8.1 × 10² 1.0 × 10⁵ 2.3 × 10³ 2.9 × 10³ 6.2 × 10¹ C1/MC3 10 μg PBS 6.0 × 10³ 2.9 × 10³ 1.7 × 10⁵ 3.8 × 10⁴ 3.2 × 10⁴ 2.1 × 10⁴ H7N9/MC3 (−14 kDa Cap) 200 μg 1.4 × 10⁴ 1.5 × 10³ 3.6 × 10⁵ 7.9 × 10³ 1.6 × 10³ 4.8 × 10² ^(†) 158 is the lower limit of detection of the nasal wash TCID₅₀ assay. All below LLOQ values were assigned a value of 79 for producing the geomean values for nasal wash. 15.8 is the lower limit of detection of the lung homogenate TCID₅₀ assay. All below LLOQ values were assigned a value of 8 for producing the geomean values for nasal wash.

There was no statistical benefit observed from the boosting vaccination compared to a single vaccination, but this is likely due to the 2-4 log reduction in viral lung titers by 49 days seen in both the single vaccination and 2 (boost) vaccination groups (Table 47).

TABLE 47 Lung Virus Burden (TCID50 Group Geographic Means)- Boosted vs. Unboosted Day 49 Day 49 with the Unboosted Day 21 Boost 200 μg Vaccine 8.0 × 10⁰ 8.0 × 10⁰ 50 μg Vaccine 9.7 × 10² 8.0 × 10⁰ 10 μg Vaccine 6.2 × 10¹ 1.1 × 10² PBS 2.1 × 10⁴ 2.2 × 10⁴ Empty Vaccine Vector 4.8 × 10² 8.0 × 10⁰ ^(†) 15.8 is the lower limit of detection of the lung homogenate TCID₅₀ assay. All below LLOQ values were assigned a value of 8 for producing the geomean values for nasal wash.

Serum was collected from each animal immediately before vaccination and challenge and analyzed by HAI assay. As seen from Table 48, a dose dependent increase was visible 7 days post vaccination, and titers increased over time. The 200-μg to14-kDa cap vaccine did provide some titer above background, between the 10-μg vaccine and PBS response. The groups receiving a second vaccination showed a dose-dependent, 3 8 fold increase in antibody titers following the second vaccination. The 200-μg to 14-kDa cap vaccine also showed an approximately 2-fold increase in antibody titers following the second vaccination. In all cases, a statistically significant increase relative to the pre-vaccination blood sample was first observed 21 days post-vaccination (p<0.05).

TABLE 48 HAI Antibody Titer Results Geomean Cohort Treatment Day 0 Day 7 Day 21 Day 49 1 200 μg Vaccine  5.00^(†) 5.45  N/A^(‡) N/A 1 50 μg Vaccine 5.00 6.48 N/A N/A 1 10 μg Vaccine 5.00 5.94 N/A N/A 1 PBS 5.00 5.00 N/A N/A 1 Empty Vaccine Vector 5.00 5.45 N/A N/A 2 200 μg Vaccine 5.00 N/A 43.62 N/A 2 50 μg Vaccine 5.00 N/A 25.94 N/A 2 10 μg Vaccine 5.00 N/A 25.94 N/A 2 PBS 5.00 N/A 5.00 N/A 2 Empty Vaccine Vector 5.00 N/A 9.35 N/A 3 200 μg Vaccine 5.00 N/A N/A 61.69 3 50 μg Vaccine 5.00 N/A N/A 33.64 3 10 μg Vaccine 5.00 N/A N/A 25.94 3 PBS 5.00 N/A N/A 5.00 3 Empty Vaccine Vector 5.00 N/A N/A 18.34 4 200 μg Vaccine 5.00 N/A 59.93 480.67 4 50 μg Vaccine 5.00 N/A 29.97 195.85 4 10 μg Vaccine 5.00 N/A 40.00 97.92 4 PBS 5.00 N/A 5.00 5.45 4 Empty Vaccine Vector 5.94 N/A 5.96 36.68 ^(†)Ten is the lower limit of detection of the HAI assay. All <10 were assigned a value of 5 for producing the geomean values. ^(‡)NA = Not applicable.

Serum samples were also analyzed by MN assay. As shown in Table 49, increases in MN titer was observed as early as 7 days post vaccination and continued to increase through 49 days post vaccination. The titers were highest in the 200-μg vaccine group, and were similar in the 50- and 10-μg groups. For the 50- and 200-μg vaccine dose groups, a statistically significant increase was observed by 7 days post-vaccination (p<0.05). For the 10-μg vaccine dose groups, the significant increase was not observed until 21 days post-vaccination (p<0.05). The 200-μg to 14-kDa cap vaccine did provide some titer above background, which was statistically significant by 49 days post vaccination (p <0.05) and were lower than the titers for the 50- and 10-μg groups. The groups receiving a second vaccination experienced a 3.0-4.5 fold increase in titers following the second vaccination. The 200-μg to 14-kDa cap vaccine also showed an approximately 1.5-fold increase in titers following the second vaccination.

TABLE 49 MN Antibody Titer Results Geomean^(†) Cohort Treatment Day 0 Day 7 Day 21 Day 49 1 H7N9/N1-methyl pseudouridine/ 15.00 33.67  N/A^(‡) N/A C1/MC3 200 μg Vaccine 1 H7N9/N1-methyl pseudouridine/ 17.38 42.29 N/A N/A C1/MC3 50 μg Vaccine 1 H7N9/N1-methyl pseudouridine/ 21.21 25.94 N/A N/A C1/MC3 10 μg Vaccine 1 PBS 19.58 18.47 N/A N/A 1 H7N9/MC3 (−14 kDa Cap) 200 ug 17.43 20.03 N/A N/A 2 H7N9/N1-methyl pseudouridine/ 14.69 N/A 92.41 N/A C1/MC3 200 μg Vaccine 2 H7N9/N1-methyl pseudouridine/ 17.49 N/A 42.50 N/A C1/MC3 50 μg Vaccine 2 H7N9/N1-methyl pseudouridine/ 15.07 N/A 43.48 N/A C1/MC3 10 μg Vaccine 2 PBS 17.89 N/A 13.60 N/A 2 H7N9/MC3 (−14 kDa Cap) 200 μg 18.52 N/A 17.43 N/A 3 H7N9/N1-methyl pseudouridine/ 15.51 N/A N/A 160.08 C1/MC3 200 μg Vaccine 3 H7N9/N1-methyl pseudouridine/ 13.16 N/A N/A 89.80 C1/MC3 50 μg Vaccine 3 H7N9/N1-methyl pseudouridine/ 13.12 N/A N/A 77.51 C1/MC3 10 μg Vaccine 3 PBS 12.70 N/A N/A 10.68 3 H7N9/MC3 (−14 kDa Cap) 200 μg 10.33 N/A N/A 46.21 4 H7N9/N1-methyl pseudouridine/ 10.33 N/A 63.44 697.88 C1/MC3 200 μg Vaccine 4 H7N9/N1-methyl pseudouridine/ 10.68 N/A 29.99 273.04 C1/MC3 50 μg Vaccine 4 H7N9/N1-methyl pseudouridine/ 10.68 N/A 31.97 232.65 C1/MC3 10 μg Vaccine 4 PBS 12.01 N/A 11.03 10.68 4 H7N9/MC3 (−14 kDa Cap) 200 μg 11.78 N/A 16.47 69.06 ^(†)20 is the lower limit of detection of the MN assay. All <20 were assigned a value of 10 for producing the geomean values. ^(‡)N/A = Not applicable.

Quite surprisingly, the vaccine constructs of the invention reduced viral titers in the lungs when exposed to virus just 7 days following vaccination. Statistically significant increases in antibody titer as measured by HAI and MN were detected as early as 7 days following vaccination. A second vaccination (i.e., booster) did increase antibody titers, but did not statistically reduce the viral titer, as a single vaccination eliminated all virus in most animals. The −14 kDa cap vaccine at 200 μg/animal provided less protection than 10-μg full vaccine, but did reduce viral burden in the lung and increased antibody titers, both relative to PBS control.

While the present invention has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the invention.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, section headings, the materials, methods, and examples are illustrative only and not intended to be limiting.

It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the invention in its broader aspects. 

The invention claimed is:
 1. A method of vaccinating a subject comprising administering to the subject a nucleic acid vaccine comprising one or more messenger ribonucleic acid (mRNA) polynucleotides comprising an open reading frame encoding an antigenic polypeptide that is derived from an infectious agent, wherein the mRNA polynucleotide is not self-replicating RNA, wherein the mRNA polynucleotides are formulated within a cationic lipid nanoparticle having a molar ratio of about 20-60% ionizable cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5-15% PEG-modified lipid, wherein the nucleic acid vaccine elicits an immune response having a longer lasting antibody titer than an antibody titer elicited by a reference nucleic acid vaccine comprising the one or more mRNA polynucleotides not formulated within a cationic lipid nanoparticle having a molar ratio of about 20-60% ionizable cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5-15% PEG-modified lipid.
 2. The method of claim 1, wherein the method comprises administering to the subject a single dosage of between 0.001 mg/kg and 0.005 mg/kg of the nucleic acid vaccine in an effective amount to vaccinate the subject.
 3. The method of claim 1, wherein the open reading frame is codon-optimized.
 4. The method of claim 1, wherein the ionizable cationic lipid nanoparticle has a polydispersity value of less than 0.4.
 5. The method of claim 1, wherein the polynucleotide has a poly-A tail of 80-250 nucleotides in length.
 6. The method of claim 1, wherein a second dose of the nucleic acid vaccine is administered to the subject.
 7. The method of claim 1, wherein the mRNA polynucleotide includes a chemical modification selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine, and 2′-O-methyl uridine.
 8. The method of claim 1, wherein the mRNA polynucleotide includes from about 500 to about 2,000 nucleotides.
 9. The method of claim 1, wherein a single dosage of between 25 ug/kg and 400 ug/kg of the nucleic acid vaccine is administered to the subject in an effective amount to vaccinate the subject.
 10. The method of claim 1, wherein the vaccine is administered to the subject via a route selected from the group consisting of intramuscular administration, intradermal administration and subcutaneous administration.
 11. The method of claim 1, wherein the method of producing an antigen specific immune response involves a single administration of the vaccine. 